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Background and Objectives: Cerebral amyloid angiopathy (CAA) is common in older adults and is associated with dementia. Less is known whether this association is mediated by Alzheimer disease (AD) neuropathologic changes, the examination of which was the objective of this study., Methods: This was a retrospective cross-sectional examination of the Kaiser Permanente Washington database of the Adult Changes in Thought (ACT) autopsy cohort with information on CAA, dementia, the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) (amyloid neuritic plaques), and Braak (tau neurofibrillary tangles). CAA was diagnosed by immunohistochemistry and dementia by ACT Consensus Diagnostic Conference. AD neuropathology was categorized by CERAD scores and Braak stages. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% CIs of the associations of CAA with dementia, adjusting for age at death and sex, and with additional adjustments separately for CERAD scores (moderate-severe vs mild-absent), Braak stages (V-VI vs 0-IV), APOE ε4, and stroke. Formal mediation analyses were conducted to estimate age-sex-adjusted OR (95% CI) for natural indirect effects (NIEs) of CERAD scores and Braak stages., Results: The 848 participants had a mean age of 86.7 ± 4.6 years at death, and 57.6% were female. CAA was present in 322 participants (38.0%), of whom 152, 145, and 25 had mild, moderate, and severe CAA, respectively. Dementia was present in 384 participants (45.3%), of whom 317 had AD. Dementia was more common in those with CAA than without (53.7% vs 40.1%; age-sex-adjusted OR 1.57, 95% CI 1.18-2.10). This association remained significant after separate adjustment for other covariates but lost significance when adjusted for CERAD scores (OR 1.27, 95% CI 0.93-1.71) and Braak stages (OR 0.96, 95% CI 0.69-1.33). Findings from our formal mediation analyses show that ORs (95% CIs) for NIE of CERAD scores and Braak stages were 1.25 (1.13-1.37) and 1.63 (1.38-1.88), respectively, and CERAD scores and Braak stages mediated 53% and 111% of the total association, respectively., Discussion: We observed a significant association between CAA and dementia that disappeared when adjusted for CERAD or Braak stages. Findings from our mediation analyses suggest that the CAA-dementia association may be potentially mediated by AD neuropathologic changes. This hypothesis needs to be tested in future mechanistic studies in AD accounting for unmeasured confounders.

Alzheimer's disease is a complex neurodegenerative condition characterized by the accumulation of amyloid beta plaques, leading to memory loss, cognitive decline, and impaired autonomous behavior. Despite extensive research, an effective treatment remains elusive. The buildup of amyloid beta plaques (Aβ42) in the brain causes oxidative stress and disrupts normal molecular signaling, adversely affecting neuron function. Previous research has identified factors that can either exacerbate or mitigate neurodegenerative diseases. Our study aimed to uncover new factors involved in the pathogenesis of Alzheimer's disease. Using Drosophila as a model organism, we employed the Gal4/UAS system to express human Aβ42 in the flies' retinal neurons which led to neurodegenerative changes in their compound eyes. To identify genetic modifiers, we conducted a screen by co-expressing microRNAs and found that miR-282 acts as a suppressor. Overexpressing miR-282 in the GMR > Aβ42 background reduced Aβ42-induced neurodegeneration. Further analysis using prediction tools and RNA interference experiments identified three potential downstream targets of miR-282: calpain-B, knot, and scabrous. Downregulating these genes via RNA interference in the GMR > Aβ42 background mitigated neurodegeneration. Our research highlights miR-282 as a novel molecule that may influence the progression of Alzheimer's disease, offering potential avenues for future therapeutic or diagnostic developments., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Proteolytic processing of amyloid precursor protein (APP) plays a critical role in the pathogenesis of Azheimer's disease (AD). Sequential cleavage of APP by β and γ secretases leads to generation of Aβ40 (non-amyloidogenic) and Aβ42 (amyloidogenic) peptides. Despite intense studies, the biological function of these peptides and the mechanism of Aβ42 toxicity is poorly understood. In the previous publications we proposed that association of Aβ peptides with the endosomal membranes may have important implications for pathogenesis of AD (Kim and Bezprozvanny, IJMS, 2021, vol 22, 13600; Kim and Bezprozvanny, IJMS, 2023, vol 24, 2092). To understand potential biological importance of such interaction, we focused on the region of Aβ peptides involved in peri-membrane association (E682 to N698). We discovered that association of this region with the membranes is reminiscent of several known anti-microbial peptides (AMP) such as PA13, Aurein1.2 and BP100. Our analysis further revealed that energy of peri-membrane association of Aβ40 is significantly weaker than for Aβ42 or AMP peptides, but it can be increased in the presence of non-amyloidogenic FAD mutations or in the presence of cholesterol in the membrane. Based on similarity with established mechanism of action of AMP peptides, we propose that Aβ peptides affect the curvature of endosomal membranes and shift the balance between endosomal recycling to plasma membrane and late endosomal/lysosomal pathway. We further propose that these effects are enhanced as a result of non-amyloidogenic FAD mutations in the sequence of Aβ peptides or in the presence of cholesterol in the membrane. The proposed model provides potential mechanistic explanation to synaptic defects induced by increased levels of Aβ42, by non-amyloidogenic FAD mutations in APP and by age-related increase in the levels of cholesterol in the brain., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:I.B. is a member of Neurodon SAB and holds Neurodon stock or stock options., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Neuronal cell demise represents a prevalent occurrence throughout the advancement of Alzheimer's disease (AD). However, the mechanism of triggering the death of neuronal cells remains unclear. Its potential mechanisms include aggregation of soluble amyloid-beta (Aβ) to form insoluble amyloid plaques, abnormal phosphorylation of tau protein and formation of intracellular neurofibrillary tangles (NFTs), neuroinflammation, ferroptosis, oxidative stress, liquid-liquid phase separation (LLPS) and metal ion disorders. Among them, ferroptosis is an iron-dependent lipid peroxidation-driven cell death and emerging evidences have demonstrated the involvement of ferroptosis in the pathological process of AD. The sensitivity to ferroptosis is tightly linked to numerous biological processes. Moreover, emerging evidences indicate that LLPS has great impacts on regulating human health and diseases, especially AD. Soluble Aβ can undergo LLPS to form liquid-like droplets, which can lead to the formation of insoluble amyloid plaques. Meanwhile, tau has a high propensity to condensate via the mechanism of LLPS, which can lead to the formation of NFTs. In this review, we summarize the most recent advancements pertaining to LLPS and ferroptosis in AD. Our primary focus is on expounding the influence of Aβ, tau protein, iron ions, and lipid oxidation on the intricate mechanisms underlying ferroptosis and LLPS within the domain of AD pathology. Additionally, we delve into the intricate cross-interactions that occur between LLPS and ferroptosis in the context of AD. Our findings are expected to serve as a theoretical and experimental foundation for clinical research and targeted therapy for AD., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Alzheimer's disease (AD) is one of the most debilitating age-related disorders that affect people globally. It impacts social and cognitive behavior of the individual and is characterized by phosphorylated tau and Aβ accumulation. Astrocytesmaintain a quiescent, anti-inflammatory state on anatomical level, expressing few cytokines and exhibit phagocytic activity to remove misfolded proteins. But in AD, in response to specific stimuli, astrocytes overstimulate their phagocytic character with overexpressing cytokine gene modules. Upon interaction with generated Aβ and neurofibrillary tangle, astrocytes that are continuously activated release a large number of inflammatory cytokines. This cytokine storm leads to neuroinflammation which is also one of the recognizable features of AD. Astrogliosis eventually promotes cholinergic dysfunction, calcium imbalance, oxidative stress and excitotoxicity. Furthermore, C5aR1, Lcn2/, BDNF/TrkB and PPARα/TFEB signaling dysregulation has a major impact on the disease progression. This review clarifies numerous ways that lead to astrogliosis, which is stimulated by a variety of processes that exacerbate AD pathology and make it a suitable target for AD treatment. Drugs under clinical and preclinical investigations that target several pathways managing astrogliosis and are efficacious in ameliorating the pathology of the disease are also included in this study. D-ALA2GIP, TRAM-34, Genistein, L-serine, MW150 and XPro1595 are examples of few drugs targeting astrogliosis. Therefore, this study may aid in the development of a potent therapeutic agent for ameliorating astrogliosis mediated AD progression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: The discovery of the glymphatic system, crucial for cerebrospinal and interstitial fluid exchange, has enhanced our grasp of brain protein balance and its potential role in neurodegenerative disease prevention and therapy. Detecting early neurodegenerative shifts via noninvasive biomarkers could be key in identifying at-risk individuals for Alzheimer's disease (AD). Our research explores a diffusion tensor imaging (DTI) method that measures cortical mean diffusivity (cMD), potentially a more sensitive indicator of neurodegeneration than traditional macrostructural methods., Materials and Methods: We analyzed 67 post-traumatic stress disorder (PTSD)-diagnosed veterans from the Alzheimer's Disease Neuroimaging Initiative database. Participants underwent structural MRI, DTI, Aβ PET imaging, and cognitive testing. We focused on the DTI-ALPS technique to assess glymphatic function and its relation to cMD, cortical Aβ accumulation, and thickness, accounting for age and APOE ε4 allele variations., Results: The cohort, all male with an average age of 68.1 (SD 3.4), showed a strong inverse correlation between DTI-ALPS and cMD in AD-affected regions, especially in the entorhinal, parahippocampal, and fusiform areas. Higher DTI-ALPS readings were consistently linked with greater cortical thickness, independent of Aβ deposits and genetic risk factors. Age and cMD emerged as inversely proportional predictors of DTI-ALPS, indicating a complex interaction with age., Conclusion: The study confirms a meaningful association between glymphatic efficiency and cMD in AD-sensitive zones, accentuating cortical microstructural alterations in PTSD. It positions DTI-ALPS as a viable biomarker for assessing glymphatic function in PTSD, implicating changes in DTI-ALPS as indicative of glymphatic impairment., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) remains a pressing global health concern, necessitating comprehensive investigations into its underlying molecular mechanisms. While the late-stage pathophysiology of this disease is well understood, it is crucial to examine the role of amyloid beta oligomers (Aβo), which form in the brain during the early stages of disease development. These toxic oligomers could affect neuronal viability and generate oxidative stress in the brain. In this study, we exposed SHSY-5Y cells to Aβo. The increase in intracellular reactive oxygen species and apoptosis observed in Aβo-treated cells mimics the early stages of AD. Comprehensive proteomic profiling identified 2966 differentially expressed proteins, with 123 significantly modulated. Utilizing the NeuroPro database, we identified 80 confirmed AD-related proteins and 43 novel candidates. Seven AD-related proteins with a NeuroPro score ≥ 5 were shortlisted. Furthermore, these proteins are found to be associated with Aβ plaques in AD brains. VGF, LTF, PARP1, and MAOA have been implicated in various mechanisms underlying AD, including synaptic plasticity, iron homeostasis, DNA repair, and neurotransmitter degradation. Our study also revealed the involvement of less-explored proteins like MYH9, CISD1, and SNRNP70, which play critical roles in cytoskeletal dynamics, mitochondrial function, and RNA splicing, respectively. These findings underscore the complex pathophysiology of AD, highlighting potential biomarkers and therapeutic targets for early intervention. The present study advances the understanding of Aβo-induced oxidative stress and neuronal damage, providing a foundation for future research into early-stage AD diagnosis and subsequent treatment strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Alzheimer disease (AD) is associated with a 2 to 3-fold increased risk of developing late-onset focal epilepsy, yet it remains unclear how development of focal epilepsy in AD is related to AD pathology. The objective of this study was to examine spatial relationships between the epileptogenic zone and tau deposition, amyloid deposition, and brain atrophy in individuals with AD who developed late-onset, otherwise unexplained focal epilepsy. We hypothesized that if network hyperexcitability is mechanistically linked to AD pathology, then there would be increased tau and amyloid deposition within the epileptogenic hemisphere., Methods: In this cross-sectional study, we performed tau and amyloid PET imaging, brain MRI, and overnight scalp EEG in individuals with early clinical stages of AD who developed late-onset, otherwise unexplained focal epilepsy (AD-Ep). Participants were referred from epilepsy and memory disorders clinics at our institutions. We determined epilepsy localization based on EEG findings and seizure semiology. We quantified tau deposition, amyloid deposition, and atrophy across brain regions and calculated asymmetry indices for these measures. We compared findings in AD-Ep with those in a control AD group without epilepsy (AD-NoEp)., Results: The AD-Ep group included 8 individuals with a mean age of 69.5 ± 4.2 years at PET imaging. The AD-NoEp group included 14 individuals with a mean age of 71.7 ± 9.8 years at PET imaging. In AD-Ep, we found a highly asymmetric pattern of tau deposition, with significantly greater tau in the epileptogenic hemisphere. Amyloid deposition and cortical atrophy were also greater in the epileptogenic hemisphere, although the magnitudes of asymmetry were reduced compared with tau. Compared with AD-NoEp, the AD-Ep group had significantly greater tau asymmetry and trends toward greater asymmetry of amyloid and atrophy. AD-Ep also had significantly greater amyloid burden bilaterally and trends toward greater tau burden within the epileptogenic hemisphere, compared with AD-NoEp., Discussion: Our results reveal a spatial association between the epileptogenic focus and tau deposition, amyloid deposition, and neurodegeneration in early clinical stages of AD. Within the limitations of a cross-sectional study with small sample sizes, these findings contribute to our understanding of the clinicopathologic heterogeneity of AD, demonstrating an association between focal epilepsy and lateralized pathology in AD.

Down syndrome (DS) is the most common genetic cause of intellectual impairment, characterised by an extra copy of chromosome 21. After the age of 40, DS individuals are highly susceptible to accelerated ageing and the development of early-onset Alzheimer-like neuropathology. In the context of DS, the brain presents a spectrum of neuropathological mechanisms and metabolic anomalies. These include heightened desensitisation of brain insulin and insulin-like growth factor-1 (IGF-1) reactions, compromised mitochondrial functionality, escalated oxidative stress, reduced autophagy, and the accumulation of amyloid beta and tau phosphorylation. These multifaceted factors intertwine to shape the intricate landscape of DS-related brain pathology. Altered brain insulin signalling is linked to Alzheimer's disease (AD). This disruption may stem from anomalies in the extracellular aspect (insulin receptor) or the intracellular facet, involving the inhibition of insulin receptor substrate 1 (IRS1). Both domains contribute to the intricate mechanism underlying this dysregulation. The PI3K-Akt/mammalian target of the rapamycin (mTOR) axis is a crucial intracellular element of the insulin signalling pathway that connects numerous physiological processes in the cell cycle. In age-related neurodegenerative disorders like AD, aberrant modulation of the PI3K-Akt signalling cascade is a key factor contributing to their onset. Aberrant and sustained hyperactivation of the PI3K/Akt-mTOR axis in the DS brain is implicated in early symptoms of AD development. Targeting the PI3K-Akt/mTOR pathway may help delay the onset of early-onset AD in individuals with DS, offering a potential way to slow disease progression and enhance their quality of life., Competing Interests: Declaration of competing interest The authors report no conflict of interest concerning the material or methods used in this study or the findings specified in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A significant quantity of substance P (SP) and its receptor, the neurokinin 1 (NK1) receptors are found in the brain. SP is a neuropeptide distributed in the central nervous system and functions as a neurotransmitter, neuromodulator, and neurotrophic factor. The concentrations of SP in the brain and cerebrospinal fluid fluctuate in individuals with Alzheimer's disease (AD). SP is an endogenous ligand for NK1 receptor, enhancing the expression of toll-like receptors (TLR) and vice versa. So, both pathways are interconnected, where activation of one pathway activates the second pathway. Researchers have observed the interaction of TLR with SP in the pathophysiology of AD. Thus, this review discusses various TLRs involved in regulating amyloid processing and its interaction with SP in AD. Further, in AD pathology, SP can regulate the non-amyloidogenic pathway. Recent studies have also demonstrated the capacity of SP in regulating voltage-gated potassium channel currents, emphasizing SP's neuroprotective ability. Therefore, we corroborate the findings linking the SP, NK1R, and TLRs in AD., Competing Interests: Declaration of competing interest The authors report there is no competing interest to declare with respect to the research, authorship and/or publication of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD), caused by amyloid beta (Aβ) plaques and Tau tangles, is a neurodegenerative disease characterized by progressive memory impairment and cognitive dysfunction. High-fat diet (HFD), which induces type 2 diabetes, exacerbates Aβ plaque deposition in the brain. To investigate the function of HFD in Tau-mediated AD, we fed an HFD to the Drosophila Tau model and found that HFD aggravates Tau-induced neurological phenotypes. Since microRNAs (miRNAs) are biomarkers for diabetes and AD, we evaluated the expression levels of common miRNAs of HFD and AD in HFD-fed Tau model fly brains. Among the common miRNAs, the expression levels of Let-7 and miR-34 were increased. We found that the inhibition of these miRNAs alleviates Tau-mediated AD phenotypes. Our research provides valuable insights into how HFD accelerates tau toxicity. Additionally, our work highlights the therapeutic potential of targeting Let-7 and miR-34 to develop innovative treatment approaches for AD., Competing Interests: Declaration of competing interest The authors have no financial interests in this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Psychotic symptoms (hallucinations and delusions) are a type of neuropsychiatric symptom found during Alzheimer's Disease (AD)., Objective: This systematic review aims to comprehensively capture, analyse, and evaluate the body of evidence that has investigated associations between brain regions/networks and psychotic symptoms in AD., Methods: The protocol, created according to the PRISMA guidelines, was pre-registered on OSF (https://osf.io/tg8xp/). Searches were performed using PubMed, Web of Science and PsycInfo. A partial coordinate-based meta-analysis (CBMA) was performed based on data availability., Results: Eighty-two papers were selected: delusions were found to be associated mainly with right fronto-temporal brain regions and the insula; hallucinations mainly with fronto-occipital areas; both were frequently associated with the anterior cingulate cortex. The CBMA, performed on the findings of fourteen papers on delusions, identified a cluster in the frontal lobe, one in the putamen, and a smaller one in the insula., Conclusions: The available evidence highlights that key brain regions, predominantly in the right frontal lobe, the anterior cingulate cortex, and temporo-occipital areas, appear to underpin the different manifestations of psychotic symptoms in AD and MCI. The fronto-temporal areas identified in relation to delusions may underpin a failure to assimilate correct information and consider alternative possibilities (which might generate and maintain the delusional belief), and dysfunction within the salience network (anterior cingulate cortex and insula) may suggest a contribution for how internal and external stimuli are identified; the fronto-occipital areas linked to hallucinations may indicate diminished sensory processing and non-optimal predictive processing, that together contribute to misinterpretation of stimuli and misperceptions; the fronto-temporal and occipital areas, as well as the anterior cingulate cortex were linked to the psychotic cluster., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest with respect to the research, authorship, or publication of this article., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Alzheimer's disease (AD) is a prevalent and debilitating brain disorder that worsens progressively with age, characterized by cognitive decline and memory impairment. The accumulation of amyloid-beta (Aβ) leading to amyloid plaques and hyperphosphorylation of Tau, resulting in intracellular neurofibrillary tangles (NFTs), are primary pathological features of AD. Despite significant research investment and effort, therapies targeting Aβ and NFTs have proven limited in efficacy for treating or slowing AD progression. Consequently, there is a growing interest in non-invasive therapeutic strategies for AD prevention. Exercise, a low-cost and non-invasive intervention, has demonstrated promising neuroprotective potential in AD prevention. Astrocytes, among the most abundant glial cells in the brain, play essential roles in various physiological processes and are implicated in AD initiation and progression. Exercise delays pathological progression and mitigates cognitive dysfunction in AD by modulating astrocyte morphological and phenotypic changes and fostering crosstalk with other glial cells. This review aims to consolidate the current understanding of how exercise influences astrocyte dynamics in AD, with a focus on elucidating the molecular and cellular mechanisms underlying astrocyte remodeling. The review begins with an overview of the neuropathological changes observed in AD, followed by an examination of astrocyte dysfunction as a feature of the disease. Lastly, the review explores the potential therapeutic implications of exercise-induced astrocyte remodeling in the context of AD., Competing Interests: Declaration of competing interest The authors have declared that no competing interest exists., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In this issue of the Journal of Experimental Medicine, Cao et al. (https://doi.org/10.1084/jem.20240386) demonstrate that the connection between the eye and the brain goes beyond the impulses carried by the optic nerve and that in Alzheimer's disease (AD), the influx of toxic Aβ from the brain to the retina underlies AD-induced retinal degeneration., (© 2024 Walsh.)

The eye is closely connected to the brain, providing a unique window to detect pathological changes in the brain. In this study, we discovered β-amyloid (Aβ) deposits along the ocular glymphatic system in patients with Alzheimer's disease (AD) and 5×FAD transgenic mouse model. Interestingly, Aβ from the brain can flow into the eyes along the optic nerve through cerebrospinal fluid (CSF), causing retinal degeneration. Aβ is mainly observed in the optic nerve sheath, the neural axon, and the perivascular space, which might represent the critical steps of the Aβ transportation from the brain to the eyes. Aquaporin-4 facilitates the influx of Aβ in brain-eye transport and out-excretion of the retina, and its absence or loss of polarity exacerbates brain-derived Aβ induced damage and visual impairment. These results revealed brain-to-eye Aβ transport as a major contributor to AD retinopathy, highlighting a new therapeutic avenue in ocular and neurodegenerative disease., (© 2024 Cao et al.)

In recent years, the glymphatic system has received increasing attention due to its possible implications in biological mechanisms associated with neurodegeneration. In the field of human brain mapping, this led to the development of diffusion tensor image analysis along the perivascular space (DTI-ALPS) index. While this index has been repeatedly used to investigate possible differences between neurodegenerative disorders and healthy controls, a comprehensive evaluation of its stability across multiple measurements and different disorders is still missing. In this study, we perform a Bayesian meta-analysis aiming to assess the consistency of the DTI-ALPS results previously reported for 12 studies on Parkinson's disease and 11 studies on Alzheimer's disease. We also evaluated if the measured value of the DTI-ALPS index can quantitatively inform the diagnostic process, allowing disambiguation between these two disorders. Our results, expressed in terms of Bayes' Factor values, confirmed that the DTI-ALPS index is consistent in measuring the different functioning of the glymphatic system between healthy subjects and patients for both Parkinson's disease (Log10(BF10) = 30) and Alzheimer's disease (Log10(BF10) = 10). Moreover, we showed that the DTI-ALPS can be used to compare these two disorders directly, therefore providing a first proof of concept supporting the reliability of taking into consideration this neuroimaging measurement in the diagnostic process. Our study underscores the potential of the DTI-ALPS index in advancing our understanding of neurodegenerative pathologies and enhancing clinical diagnostics., (© 2024. The Author(s).)

Genome-wide association studies have identified a protective mutation in the phospholipase C gamma 2 (PLCG2) gene which confers protection against Alzheimer's disease (AD)-associated cognitive decline. Therefore, PLCG2, which is primarily expressed in immune cells, has become a target of interest for potential therapeutic intervention. The protective allele, known as P522R, has been shown to be hyper-morphic in microglia, increasing phagocytosis of amyloid-beta (Aβ), and increasing the release of inflammatory cytokines. However, the effect of this protective mutation on peripheral tissue-resident macrophages, and the extent to which sex modifies this effect, has yet to be assessed. Herein, we show that peripheral macrophages carrying the P522R mutation do indeed show functional differences compared to their wild-type (WT) counterparts, however, these alterations occur in a sex-dependent manner. In macrophages from females, the P522R mutation increases lysosomal protease activity, cytokine secretion, and gene expression associated with cytokine secretion and apoptosis. In contrast, in macrophages from males, the mutation causes decreased phagocytosis and lysosomal protease activity, modest increases in cytokine secretion, and induction of gene expression associated with negative regulation of the immune response. Taken together, these results suggest that the mutation may be conferring different effects dependent on sex and cell type, and highlight the importance of considering sex as a biological variable when assessing the effects of genetic variants and implications for potential immune system-targeted therapies., (© 2024. The Author(s).)

Background: The Interleukin-6 (IL-6)-signal transducer and activator of transcription 3 (STAT3) pathway, along with the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, are critical contributors to neuroinflammation in Alzheimer's disease (AD). Although previous research outside the context of AD has indicated that the IL-6-STAT3 pathway may regulate the cGAS-STING pathway, the exact molecular mechanisms through which IL-6-STAT3 influences cGAS-STING in AD are still not well understood., Methods: The activation of the IL-6-STAT3 and cGAS-STING pathways in the hippocampus of 5×FAD and WT mice was analyzed using WB and qRT-PCR. To explore the effects of IL-6 deficiency, Il6 +/- mice were crossed with 5×FAD mice, and the subsequent impact on hippocampal STAT3 pathway activity, cGAS-STING pathway activation, amyloid pathology, neuroinflammation, and cognitive function was evaluated through WB, qRT-PCR, immunohistochemistry, ThS staining, ELISA, and behavioral tests. The regulatory role of STAT3 in the transcription of the Cgas and Sting genes was further validated using ChIP-seq and ChIP-qPCR on hippocampal tissue from 5×FAD and Il6 -/- : 5×FAD mice. Additionally, in the BV2 microglial cell line, the impact of STAT3 activation on the transcriptional regulation of Cgas and Sting genes, as well as the production of inflammatory mediators, was examined through WB and qRT-PCR., Results: We observed marked activation of the IL-6-STAT3 and cGAS-STING pathways in the hippocampus of AD mice, which was attenuated in the absence of IL-6. IL-6 deficiency reduced beta-amyloid deposition and neuroinflammation in the hippocampus of AD mice, contributing to cognitive improvements. Further analysis revealed that STAT3 directly regulates the transcription of both the Cgas and Sting genes. These findings suggest a potential mechanism involving the STAT3-cGAS-STING pathway, wherein IL-6 deficiency mitigates neuroinflammation in AD mice by modulating this pathway., Conclusion: These findings indicate that the STAT3-cGAS-STING pathway is critical in mediating neuroinflammation associated with AD and may represent a potential therapeutic target for modulating this inflammatory process in AD., (© 2024. The Author(s).)

Alzheimer´s disease (AD) is characterized by neuronal function loss and degeneration. The integrity of the axon initial segment (AIS) is essential to maintain neuronal function and output. AIS alterations are detected in human post-mortem AD brains and mice models, as well as, neurodevelopmental and mental disorders. However, the mechanisms leading to AIS deregulation in AD and the extrinsic glial origin are elusive. We studied early postnatal differences in AIS cellular/molecular mechanisms in wild-type or APP/PS1 mice and combined neuron-astrocyte co-cultures. We observed AIS integrity alterations, reduced ankyrinG expression and shortening, in APP/PS1 mice from P21 and loss of AIS integrity at 21 DIV in wild-type and APP/PS1 neurons in the presence of APP/PS1 astrocytes. AnkyrinG decrease is due to mRNAs and protein reduction of retinoic acid synthesis enzymes Rdh1 and Aldh1b1, as well as ADNP (Activity-dependent neuroprotective protein) in APP/PS1 astrocytes. This effect was mimicked by wild-type astrocytes expressing ADNP shRNA. In the presence of APP/PS1 astrocytes, wild-type neurons AIS is recovered by inhibition of retinoic acid degradation, and Adnp-derived NAP peptide (NAPVSIPQ) addition or P2X7 receptor inhibition, both regulated by retinoic acid levels. Moreover, P2X7 inhibitor treatment for 2 months impaired AIS disruption in APP/PS1 mice. Our findings extend current knowledge on AIS regulation, providing data to support the role of astrocytes in early postnatal AIS modulation. In conclusion, AD onset may be related to very early glial cell alterations that induce AIS and neuronal function changes, opening new therapeutic approaches to detect and avoid neuronal function loss., (© 2024. The Author(s).)

Objectives: Based on the literature, tensor-based morphometry (TBM) parameters were related to neurocognitive functions such as memory, learning, language ability, and executive functions. The present study aims to evaluate the associations between TBM indices with executive functions, memory, language, and visuospatial abilities and the value of TBM in the clinical diagnosis of Alzheimer's disease (AD) among individuals with Alzheimer's disease continuum and mild cognitive impairment (MCI) from Alzheimer's Disease Neuroimaging Initiative (ADNI)., Methods: The authors used ADNI-memory (ADNI-MEM), ADNI-executive functions (ADNI-EF), ADNI-language (ADNI-LAN), and ADNI-visuospatial (ADNI-VS) composite scores. TBM parameters, including measure 1, which represents average within a statistically defined region-of-interest inside the temporal lobes and measure 2 which indicates average within an anatomically defined region-of-interest including bilateral temporal lobes were utilized in the current study. Statistical analysis was performed using IBM SPSS Statistics version 26, and Pearson's correlation, Bonferroni's correction, and multiple linear regression were utilized for data analysis. P <0.05 was considered statistically significant., Results: After screening 800 participants, 270 (151 men, 119 women) were selected for a study with TBM scores and cognition-related assessments at 6, 12, and 24 months. Groups included healthy controls (n=53), MCI (n=158), and Alzheimer's Disease (AD) (n=59). TBM indices correlated with cognitive scores in MCI and AD groups but not healthy controls. Changes in TBM indices and cognitive scores were significantly correlated in MCI and AD groups over 24 months. TBM indices were weak predictors of cognitive decline at all time points., Conclusions: TBM can help physicians diagnose MCI and AD early. However, TBM could not strongly predict cognitive functions decline at all time points., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Alzheimer disease (AD) is a prevalent neurodegenerative disorder that affects synapses and leads to progressive cognitive decline. The role of N-methyl-D-aspartic acid (NMDA) receptors in the pathogenesis of AD is well-established as they contribute to excitotoxicity and neurodegeneration in the pathological process of extrasynaptic glutamate concentration. However, the therapeutic potential of the NMDA receptor antagonist memantine in rescuing synaptic damage is limited. Research indicates that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors also play a significant role in AD. Abnormal transcription, expression, and localization of AMPA receptors lead to synaptic dysfunction and damage, contributing to early cognitive impairment in AD patients. Understanding the impact of AMPA receptors on AD pathogenesis and exploring the potential for the development of AMPA receptor-targeting drugs are crucial. This review aims to consolidate recent research findings on AMPA receptors in AD, elucidate the current state of AMPA receptor research and lay the foundation for future basic research and drug development., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aquaporin-4 (AQP4) is hypothesized to be a component of the glymphatic system, a pathway for removing brain interstitial solutes like amyloid-β (Aβ). Evidence exists that genetic variation of AQP4 impacts Aβ clearance, clinical outcome in Alzheimer's disease as well as sleep measures. We examined whether a risk score calculated from several AQP4 single-nucleotide polymorphisms (SNPs) is related to Aβ neuropathology in older cognitively unimpaired white individuals. We used a machine learning approach and explainable artificial intelligence to extract information on synergistic effects of AQP4 SNPs on brain amyloid burden from the ADNI cohort. From this information, we formulated a sex-specific AQP4 SNP-based risk score and evaluated it using data from the screening process of the A4 study. We found in both cohorts significant associations of the risk score with brain amyloid burden. The results support the hypothesis of an involvement of the glymphatic system, and particularly AQP4, in brain amyloid aggregation pathology. They suggest also that different AQP4 SNPs exert a synergistic effect on the build-up of brain amyloid burden., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Apolipoprotein E ε4 (APOE4) is a strong genetic risk factor of Alzheimer's disease and metabolic dysfunction. However, whether APOE4 and markers of metabolic dysfunction synergistically impact the deterioration of white matter (WM) integrity in older adults remains unknown. In the UK Biobank data, we conducted a multivariate analysis to investigate the interactions between APOE4 and 249 plasma metabolites (measured using nuclear magnetic resonance spectroscopy) with whole-brain WM integrity (measured by diffusion-weighted magnetic resonance imaging) in a cohort of 1917 older adults (aged 65.0-81.0 years; 52.4 % female). Although no main association was observed between either APOE4 or metabolites with WM integrity (adjusted P > 0.05), significant interactions between APOE4 and metabolites with WM integrity were identified. Among the examined metabolites, higher concentrations of low-density lipoprotein and very low-density lipoprotein were associated with a lower level of WM integrity (b=-0.12, CI=-0.14,-0.10) among APOE4 carriers. Conversely, among non-carriers, they were associated with a higher level of WM integrity (b=0.05, CI=0.04,0.07), demonstrating a significant moderation role of APOE4 (b =-0.18, CI=-0.20,-0.15, P<0.00001)., Competing Interests: Declaration of Competing Interest The authors declare that this manuscript, in its entirety or in part, has not been previously published or is under consideration for publication elsewhere, in any language. Each author acknowledges their responsibility for the content presented. Furthermore, the authors affirm that, if accepted, the manuscript will not be reproduced or published in the same form, whether in English or any other language, including electronic formats, without obtaining written consent from the copyright-holder. This submission adheres to ethical standards, and the authors stand committed to exclusive publication rights for the work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Neuropathologic changes of Alzheimer disease (AD) including Aβ accumulation and neuroinflammation are frequently observed in the cerebral cortex of patients with idiopathic normal pressure hydrocephalus (iNPH). We created an automated analysis platform to quantify Aβ load and reactive microglia in the vicinity of Aβ plaques and to evaluate their association with cognitive outcome in cortical biopsies of patients with iNPH obtained at the time of shunting. Aiforia Create deep learning software was used on whole slide images of Iba1/4G8 double immunostained frontal cortical biopsies of 120 shunted iNPH patients to identify Iba1-positive microglia somas and Aβ areas, respectively. Dementia, AD clinical syndrome (ACS), and Clinical Dementia Rating Global score (CDR-GS) were evaluated retrospectively after a median follow-up of 4.4 years. Deep learning artificial intelligence yielded excellent (>95%) precision for tissue, Aβ, and microglia somas. Using an age-adjusted model, higher Aβ coverage predicted the development of dementia, the diagnosis of ACS, and more severe memory impairment by CDR-GS whereas measured microglial densities and Aβ-related microglia did not correlate with cognitive outcome in these patients. Therefore, cognitive outcome seems to be hampered by higher Aβ coverage in cortical biopsies in shunted iNPH patients but is not correlated with densities of surrounding microglia., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc.)

Alzheimer's disease (AD) is linked to toxic Aβ plaques in the brain and activation of innate responses. Recent findings however suggest that the disease may also depend on the adaptive immunity, as B cells exacerbate and CD8 + T cells limit AD-like pathology in mouse models of amyloidosis. Here, by artificially blocking or augmenting CD8 + T cells in the brain of 5xFAD mice, we provide evidence that AD-like pathology is promoted by pathogenic, proinflammatory cytokines and exhaustion markers expressing CXCR6 + CD39 + CD73 +/- CD8 + T RM -like cells. The CD8 + T cells appear to act by targeting disease associated microglia (DAM), as we find them in tight complexes with microglia around Aβ plaques in the brain of mice and humans with AD. We also report that these CD8 + T cells are induced by B cells in the periphery, further underscoring the pathogenic importance of the adaptive immunity in AD. We propose that CD8 + T cells and B cells should be considered as therapeutic targets for control of AD, as their ablation at the onset of AD is sufficient to decrease CD8 + T cells in the brain and block the amyloidosis-linked neurodegeneration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Alzheimer's disease (AD) is the most common cause of dementia and is caused by various factors including amyloid-beta (Aβ) aggregation. We investigated the pharmacological effects of the ethanol extract of Potentilla fragarioides var. major (Rosaceae) (EEPF) on AD-related pathogenesis, which remain elusive. We observed the effects of EEPF on Aβ disaggregation and free-radical scavenging activities for 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) using in vitro assays, evaluated the effects of EEPF on memory loss in two animal models, and examined the molecular regulatory mechanisms of EEPF using an antibody-protein microarray in EEPF-treated neuronal cell lines. EEPF inhibited Aβ aggregation in a concentration-dependent manner and enhanced free-radical scavenging activities for ABTS and DPPH. EEPF significantly inhibited memory impairment in the passive avoidance task, Y-maze test, and Morris water maze test in scopolamine-induced short-term memory loss mice and Aβ-injected AD-like mice. Nissl staining and immunohistochemistry for NeuN and Iba-1 confirmed the neuroprotective and anti-inflammatory effects of EEPF in both animal models. In H 2 O 2 -treated HT22 hippocampal cells, EEPF significantly prevented cell damage, enhanced CaMK2, and reduced ferric reductase. In lipopolysaccharide (LPS)-stimulated BV-2 microglia, EEPF significantly inhibited LPS-induced production of inflammatory factors, such as nitric oxide, prostaglandin E2, tumor necrosis factor-α, and interleukin-6, and decreased the phosphorylation of Smad3 and cyclin D3. High-performance liquid chromatography confirmed that EEPF has five major components: neochlorogenic acid, chlorogenic acid, polydatin, isochlorogenic acid A, and buddleoside, with amounts ranging across 1.91-9.41 mg/g. EEPF may be a promising drug for treatment of AD and AD-related brain disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a common age-associated progressive neurodegenerative disorder that is implicated in the aberrant regulation of numerous circular RNAs (circRNAs). Here, we reported that circ-Bptf, a conserved circRNA derived from the Bptf gene, showed an age-dependent decrease in the hippocampus of APP/PS1 mice. Overexpression of circ-Bptf significantly reversed dendritic spine loss and learning and memory impairment in APP/PS1 mice. Moreover, we found that circ-Bptf was predominantly localized to the cytoplasm and upregulated p62 expression by binding to miR-138-5p. Furthermore, the miR-138-5p mimics reversed the decreased expression of p62 induced by the silencing of circ-Bptf. Together, our findings suggested that circ-Bptf ameliorated learning and memory impairments via the miR-138-5p/p62 axis in APP/PS1 mice. It may act as a potential player in AD pathogenesis and therapy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Recent US proposals suggest defining Alzheimer's disease (AD) based on β-amyloidosis alone. This sparked debates that echoed historical ones about the significance of brain lesions and clinical phenotype., Methods: This review covers debates on AD nosology through three key periods: AD's discovery in German-speaking countries in the early 20th century, its redefinition in Anglo-Saxon countries in the 1960s-1980s, and current debates on the biological or clinicobiological definitions of AD. Key players' opinions are focused on., Results: At the beginning of the 20th century, AD was defined as a clinicopathological entity. Debates arose around the pathological anchor, which included extended neurofibrillary tangles versus neuritic plaques (Alzheimer vs. Fischer) and its association with senile dementia (Kraepelin). In the 1960s-1980s, the debate shifted towards whether AD could be diagnosed using qualitative or quantitative neuropathological features and whether it was a unique process (Terry and Katzman) or had subtypes (Roth). The current definition proposed by the US Alzheimer's Association is based purely on biological β-amyloid abnormalities and represents a double break: from the historical clinicopathological definition of AD and from the historical emphasis on tau or combined tau and β-amyloid high levels of pathology. Conversely, the clinicobiological proposal of the International Working Group remains aligned with historical concepts of AD., Conclusions: This historical perspective illustrates the unresolved questions surrounding AD pathogenesis, role of lesions, and the clinical phenotype, especially for sporadic cases. The intense nosological debates throughout the history of AD also illustrate the diversity of theoretical frameworks for defining disease in medicine., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Alzheimer's disease, marked by memory loss and cognitive decline, is associated with amyloid-beta (Aβ) peptide accumulation in the brain. The enzyme neprilysin (NEP), crucial for Aβ degradation, decreases with age and in sporadic Alzheimer's disease, leading to increased Aβ build-up. This study hypothesized the targeting of enzyme HDAC6, believed to influence NEP activity. An in-silico study was conducted using an FDA-approved drug database, with the focus on their interaction with the HDAC6 structure. Among tested ligands, Panobinostat showed the most favourable interaction with HDAC6. In-vitro experiments on the SH-SY5Y neuronal cell line confirmed these findings, with Panobinostat inhibiting HDAC6, enhancing NEP levels, and reducing Aβ load. The study suggests Panobinostat as a potential Alzheimer's therapeutic agent, mitigating Aβ accumulation via NEP upregulation. Further research is required for comprehensive understanding and validation.Communicated by Ramaswamy H. Sarma.

Tau protein is involved in various cellular processes, including having a canonical role in binding and stabilization of microtubules in neurons. Tauopathies are neurodegenerative diseases marked by the abnormal accumulation of tau protein aggregates in neurons, as seen, for example, in conditions such as frontotemporal dementia and Alzheimer disease. Mutations in tau coding regions or that disrupt tau mRNA splicing, tau post-translational modifications and cellular stress factors (such as oxidative stress and inflammation) increase the tendency of tau to aggregate and interfere with its clearance. Pathological tau is strongly implicated in the progression of neurodegenerative diseases, and the propagation of tau aggregates is associated with disease severity. Recent technological advancements, including cryo-electron microscopy and disease models derived from human induced pluripotent stem cells, have increased our understanding of tau-related pathology in neurodegenerative conditions. Substantial progress has been made in deciphering tau aggregate structures and the molecular mechanisms that underlie protein aggregation and toxicity. In this Review, we discuss recent insights into the diverse cellular functions of tau and the pathology of tau inclusions and explore the potential for therapeutic interventions., (© 2024. Springer Nature Limited.)

Alzheimer's disease (AD) is characterized by disorders in brain energy. The lack of sufficient energy for nerve function leads to cognitive dysfunction and massive neuronal loss in AD. Ketone bodies are an alternative to glucose as a source of energy in the brain, and alternate-day fasting (ADF) promotes the production of the ketone body β-hydroxybutyric acid (βOHB). In this study, 7-month-old male WT mice and 3xTg mice underwent dietary control for 20 weeks. We found that ADF increased circulating βOHB concentrations in 3xTg mice, improved cognitive function, reduced anxiety-like behaviors, improved hippocampal synaptic plasticity, and reduced neuronal loss, Aβ oligomers and tau hyperphosphorylation. In addition, ADF improved mitochondrial bioenergetic function by promoting brain ketone metabolism and rescued brain energy deficits in 3xTg mice. A safety evaluation showed that ADF improved exercise endurance and liver and kidney function in 3xTg mice without negatively affecting muscle motor and heart functions. This study provides a theoretical basis and strong support for the application of ADF as a non-drug strategy for preventing and treating brain energy defects in the early stage of AD., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background: Chronic pain leads to tau accumulation and hippocampal atrophy, which may be moderated through inflammation. In older men, we examined associations of chronic pain with Alzheimer's disease (AD)-related plasma biomarkers and hippocampal volume as moderated by systemic inflammation., Methods: Participants were men without dementia. Chronic pain was defined as moderate-to-severe pain in 2+ study waves at average ages 56, 62, and 68. At age 68, we measured plasma amyloid-beta (Aβ42, n = 871), Aβ40 (n = 887), total tau (t-tau, n = 841), and neurofilament light chain (NfL, n = 915), and serum high-sensitivity C-reactive protein (hs-CRP, n = 968), a marker of systemic inflammation. A subgroup underwent structural MRI to measure hippocampal volume (n = 385). Analyses adjusted for medical morbidities, depressive symptoms, and opioid use., Results: Chronic pain was related to higher Aβ40 (β = 0.25, p = .009), but hs-CRP was unrelated to AD-related biomarkers (ps > .05). There was a significant interaction such that older men with both chronic pain and higher levels of hs-CRP had higher levels of Aβ42 (β = 0.36, p = .001) and Aβ40 (β = 0.29, p = .003). Chronic pain and hs-CRP did not interact to predict levels of Aβ42/Aβ40, t-tau, or NfL. Furthermore, there were significant interactions such that Aβ42 and Aβ40 were associated with lower hippocampal volume, particularly when levels of hs-CRP were elevated (hs-CRP × Aβ42: β = -0.19, p = .002; hs-CRP × Aβ40: β = -0.21, p = .001), regardless of chronic pain status., Conclusions: Chronic pain was associated with higher plasma Aβ, especially when hs-CRP was also elevated. Higher hs-CRP and Aβ levels were both related to smaller hippocampal volumes. Chronic pain, when accompanied by systemic inflammation, may elevate the risk of neurodegeneration in AD-vulnerable regions., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Few studies have focused on the association between clonal hematopoiesis of indeterminate potential (CHIP) and β-amyloid (Aβ) deposition in the brain, which causes Alzheimer's disease. We aimed to investigate the potential role of CHIP in brain Aβ deposition in Korean patients. We enrolled 58 Korean patients over 50 yrs of age with cognitive impairment who underwent brain Aβ positron emission tomography. We explored CHIP in their peripheral blood using deep-targeted next-generation sequencing. Irrespective of the presence or absence of brain Aβ deposition, mutations in DNMT3A and the C:G>T:A single-nucleotide variants were identified as the primary characteristics, which reflect aged hematopoiesis in the study population. Multivariate logistic regression revealed that the presence of CHIP was not associated with brain Aβ deposition. As both CHIP and brain Aβ deposition are associated with aging, further research is required to elucidate their possible interplay.

Alzheimer's disease (AD) is the most common neurodegenerative disease all over the world. In the last decade, accumulating proofs have evidenced that neuroinflammation is intimately implicated in the pathogenesis of AD and activation of NOD-like receptor family pyrin domain-containing 1 (NLRP1) inflammasome can induce neuronal pyroptosis and in turn lead to neuronal loss in AD. Thioredoxin-1 (Trx-1), a multifunctional molecule with anti-inflammation in human tissues, displays crucial neuroprotective roles in AD. Our previous research preliminarily found that Trx-1 inhibition enhanced the expression of NLRP1, caspase-1, and gasdermin D (GSDMD) in Aβ 25-35 -treated PC12 cells. However, it is largely unknown if Trx-1 can inhibit NLRP1-mediated neuronal pyroptosis in AD neurons. In this study, it was verified that the protein levels of NLRP1, caspase-1, and GSDMD were significantly increased in Aβ 25-35 -treated mouse HT22 and primary hippocampal neurons. Suppression of Trx-1 with PX-12, a selective inhibitor of Trx-1, or Trx-1 knockdown further activated NLRP1-mediated neuronal pyroptosis. On the contrary, lentivirus infection-mediated Trx-1 overexpression in differentiated PC12 cells dramatically reversed expression of NLRP1, caspase-1, and GSDMD. Furthermore, Trx-1 overexpression mediated by adeno-associated virus in the hippocampal tissues of APP/PS1 mice likewise attenuated the activation of NLRP1-mediated neuronal pyroptosis, as well as reduced the hippocampal deposition of Aβ and ameliorated the cognitive function of APP/PS1 mice. In conclusion, this article predicates a novel molecular mechanism by which Trx-1 exploits neuroprotection through attenuating NLRP1-mediated neuronal pyroptosis in AD models, suggesting that Trx-1 may be a promising therapeutic target for AD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Emerging studies suggest that Wnt signaling is dysregulated in the brains of AD patients, suggesting that this pathway may also contribute to disease progression. However, it remains to be determined whether alterations in the Wnt pathway are the cause or consequence of this disease and which elements of Wnt signaling mainly contribute to the appearance of AD histopathological markers early in disease compared to what occurs during normal aging. The present study aimed to describe the status of several canonical Wnt pathway components and the expression of the AD marker p-tau in the hippocampi of female and male 3xTg-AD mice during disease progression compared to those during normal aging. We analyzed the levels of the canonical Wnt components Wnt7a, Dkk-1, LRP6 and GSK3β as well as the levels of p-tau and BDNF at 3, 6, 9-12 and 18 months of age. We found a gradual increase in Dkk-1 levels during aging prior to Wnt7a and LRP5/6 depletion, which was strongly exacerbated in 3xTg-AD mice even at young ages and correlated with GSK3β activation and p-tau-S202/Thr205 expression. Dkk-1 upregulation, as well as the level of p-tau, was significantly greater in females than in males. Our results suggest that Dkk-1 upregulation is involved in the expression of several features of AD at early stages, which supports the possibility of positively modulating the canonical Wnt pathway as a therapeutic tool to delay this disease at early stages., (© 2024. The Author(s).)

Background: Alzheimer's disease and related dementias (ADRD) and osteoporosis (OP) are 2 prevalent diseases of aging with demonstrated epidemiological association, but the underlying molecular mechanisms contributing to this association are unknown., Methods: We used network analysis of bone and brain transcriptomes to discover common molecular mechanisms underlying these 2 diseases. Our study included RNA-sequencing data from the dorsolateral prefrontal cortex tissue of autopsied brains in 629 participants from ROSMAP (Religious Orders Study and the Rush Memory and Aging Project), with a subgroup of 298 meeting criteria for inclusion in 5 ADRD categories, and RNA array data from transiliac bone biopsies in 84 participants from the Oslo study of postmenopausal women. After developing each network within each tissue, we analyzed associations between modules (groups of coexpressed genes) with multiple bone and neurological traits, examined overlap in modules between networks, and performed pathway enrichment analysis to discover conserved mechanisms., Results: We discovered 3 modules in ROSMAP that showed significant associations with ADRD and bone-related traits and 4 modules in Oslo that showed significant associations with multiple bone outcomes. We found significant module overlap between the 2 networks in modules linked to signaling, tissue homeostasis, and development, and Wingless-related integration site (Wnt) signaling was found to be highly enriched in OP and ADRD modules of interest., Conclusions: These results provide translational opportunities in the development of treatments and biomarkers for ADRD and OP., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Accumulation of β-amyloid (Aβ) in the brain has been recognized as a key factor in the onset and progression of Alzheimer's disease (AD).The accumulation of Aβ in the brain catalyzes the production of reactive oxygen species (ROS), which in turn triggers oxidative damage to cellular components such as DNA, lipids, and proteins. In the present study, we investigated the protective effect of Ganoderic acid A (GA.A) against Aβ42-induced apoptosis in PC12 cells. Changes in mitochondrial membrane potential indicated that GA.A treats mitochondrial dysfunction by decreasing Aβ42 deposition and inhibiting neural protofiber tangle formation. Changes in intracellular Ca 2+ and caspase-3 indicated that GA.A reduced mitochondrial damage by Aβ42 in PC12 cells, thereby decreasing ROS accumulation and reducing Aβ protofiber-induced cytotoxicity. These features suggest that GA.A has great potential as an effective neuroprotective drug in the treatment of Alzheimer's disease., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Perivascular space (PVS) enlargement in ageing and Alzheimer's disease (AD) and the drivers of such a structural change in humans require longitudinal investigation. Elucidating the effects of demographic factors, hypertension, cerebrovascular dysfunction, and AD pathology on PVS dynamics could inform the role of PVS in brain health function as well as the complex pathophysiology of AD., Methods: We studied PVS in centrum semiovale (CSO) and basal ganglia (BG) computationally over three to four annual visits in 503 participants (255 females; mean age  = 70.78 ± 5.78) of the ongoing observational multicentre "DZNE Longitudinal Cognitive Impairment and Dementia Study" (DELCODE) cohort. We analysed data from subjects who were cognitively unimpaired (n = 401), had amnestic mild cognitive impairment (n = 71), or had AD (n = 31). We used linear mixed-effects modelling to test for changes of PVS volumes in relation to cross-sectional and longitudinal age, as well as sex, years of education, hypertension, white matter hyperintensities, AD diagnosis, and cerebrospinal-fluid-derived amyloid (A) and tau (T) status (available for 46.71%; A-T-/A + T-/A + T + n = 143/48/39)., Results: PVS volumes increased significantly over follow-ups (CSO: B = 0.03 [0.02, 0.05], p < 0.001; BG: B = 0.05 [0.03, 0.07], p < 0.001). PVS enlargement rates varied substantially across subjects and depended on the participant's age, white matter hyperintensities volumes, and amyloid and tau status. PVS volumes were higher across elderly participants, regardless of region of interest (CSO: B = 0.12 [0.02, 0.21], p = 0.017; BG: B = 0.19 [0.09, 0.28], p < 0.001). Faster BG-PVS enlargement related to lower baseline white matter hyperintensities volumes (ρ spearman  = -0.17, p FDR  = 0.001) and was more pronounced in individuals who presented with combined amyloid and tau positivity versus negativity (A + T +  > A-T-, p FDR  = 0.004) or who were amyloid positive but tau negative (A + T +  > A + T-, p FDR  = 0.07). CSO-PVS volumes increased at a faster rate with amyloid positivity as compared to amyloid negativity (A + T-/A + T +  > A-T-, p FDR  = 0.021)., Conclusion: Our longitudinal evidence supports the relevance of PVS enlargement in presumably healthy ageing as well as in AD pathology. We further discuss the region-specific involvement of white matter hyperintensities and neurotoxic waste accumulation in PVS enlargement and the possibility of additional factors contributing to PVS progression. A comprehensive understanding of PVS dynamics could facilitate the understanding of pathological cascades and might inform targeted treatment strategies., Trial Registration: German Clinical Trials Register DRKS00007966. Registered 04.05.2015 - retrospectively registered, https://drks.de/search/en/trial/DRKS00007966 ., (© 2024. The Author(s).)

Alzheimer's disease (AD) is the most common neurodegenerative disease, and a defect in neuronal plasma membrane repair could exacerbate neurotoxicity, neuronal death, and disease progression. In this study, application of AD patient cerebrospinal fluid (CSF) and recombinant human Aβ to otherwise healthy neurons induces defective neuronal plasma membrane repair in vitro and ex vivo. We identified Aβ as the biochemical component in patient CSF leading to compromised repair capacity and depleting Aβ rescued repair capacity. These elevated Aβ levels reduced expression of dysferlin, a protein that facilitates membrane repair, by altering autophagy and reducing dysferlin trafficking to sites of membrane injury. Overexpression of dysferlin and autophagy inhibition rescued membrane repair. Overall, these findings indicate an AD pathogenic mechanism where Aβ impairs neuronal membrane repair capacity and increases susceptibility to cell death. This suggests that membrane repair could be therapeutically targeted in AD to restore membrane integrity and reduce neurotoxicity and neuronal death., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

In this high-throughput proteomic study of autosomal dominant Alzheimer's disease (ADAD), we sought to identify early biomarkers in cerebrospinal fluid (CSF) for disease monitoring and treatment strategies. We examined CSF proteins in 286 mutation carriers (MCs) and 177 non-carriers (NCs). The developed multi-layer regression model distinguished proteins with different pseudo-trajectories between these groups. We validated our findings with independent ADAD as well as sporadic AD datasets and employed machine learning to develop and validate predictive models. Our study identified 137 proteins with distinct trajectories between MCs and NCs, including eight that changed before traditional AD biomarkers. These proteins are grouped into three stages: early stage (stress response, glutamate metabolism, neuron mitochondrial damage), middle stage (neuronal death, apoptosis), and late presymptomatic stage (microglial changes, cell communication). The predictive model revealed a six-protein subset that more effectively differentiated MCs from NCs, compared with conventional biomarkers., Competing Interests: Declaration of interests C.C. has received research support from GSK and EISAI. C.C. is a member of the advisory board of Circular Genomics and owns stocks in these companies. C.C. is on the advisory board of ADmit. J.L. reports speaker fees from Bayer Vital, Biogen, EISAI, TEVA, Zambon, Merck, and Roche; consulting fees from Axon Neuroscience, EISAI, and Biogen; author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers; and is inventor in a patent “Oral Phenylbutyrate for Treatment of Human 4-Repeat Tauopathies” (EP 23 156 122.6). He receives compensation for serving as chief medical officer for MODAG GmbH and is a beneficiary of the phantom share program of MODAG GmbH. E.M. reports research support received from NIA (U01AG059798), Anonymous Foundation, GHR, Alzheimer Association, Eli Lilly Eisai, and Hoffmann-La Roche and paid consulting for Eli Lilly, Alector, Alzamend, Sanofi, AstraZeneca, Hoffmann-La Roche, Grifols, and Merck., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Necroptosis is a regulated form of cell death that has been observed in Alzheimer's disease (AD) along with the classical pathological hallmark lesions of amyloid plaques and Tau neurofibrillary tangles. To understand the neurodegenerative process in AD, we studied the role of necroptosis in mouse models and primary mouse neurons. Using immunohistochemistry, we demonstrated activated necroptosis-related proteins in transgenic mice developing Tau pathology and in primary neurons from amyloid precursor protein (APP)-Tau double transgenic mice treated with phosphorylated Tau seeds derived from a patient with AD but not in APP transgenic mice that only exhibited β-amyloid deposits. Necroptosis proteins in granulovacuolar degeneration (GVD) bodies were associated with neuronal loss in mouse brain regions also known to be vulnerable to GVD in the human AD brain. Necroptosis inhibitors lowered the percentage of neurons showing GVD and reduced neuronal loss, both in transgenic mice and in primary mouse neurons. This suggests that a GVD-associated form of necroptosis that we refer to as "GVD-necroptosis" may represent a delayed form of necroptosis in AD. We propose that inhibition of necroptosis could rescue this type of neuronal death in AD.

Reduced nitric oxide (NO) bioavailability is a pathological link between obesity and Alzheimer's disease (AD). Obesity-associated metabolic and mitochondrial bioenergetic dysfunction are key drivers of AD pathology. The hypothalamus is a critical brain region during the development of obesity and dysfunction is an area implicated in the development of AD. NO is an essential mediator of blood flow and mitochondrial bioenergetic function, but the role of NO in obesity-AD is not entirely clear. We investigated diet-induced obesity in female APPswe/PS1dE9 (APP) mouse model of AD, which we treated with two different NO donors (sodium nitrite or L-citrulline). After 26 weeks of a high-fat diet, female APP mice had higher adiposity, insulin resistance, and mitochondrial dysfunction (hypothalamus) than non-transgenic littermate (wild type) controls. Treatment with either sodium nitrite or L-citrulline did not reduce adiposity but improved whole-body energy expenditure, substrate oxidation, and insulin sensitivity. Notably, both NO donors restored hypothalamic mitochondrial respiration in APP mice. Our findings suggest that NO is an essential mediator of whole-body metabolism and hypothalamic mitochondrial function, which are severely impacted by the dual insults of obesity and AD pathology., (© 2024. The Author(s).)

Synaptic dysfunction and loss are central to neurodegenerative diseases and correlate with cognitive decline. Synaptic Vesicle Protein 2A (SV2A) is a promising PET-imaging target for assessing synaptic density in vivo, but comprehensive mapping in the human brain is needed to validate its biomarker potential. This study used quantitative immunohistochemistry and Western blotting to map SV2A and synaptophysin (SYP) densities across six cortical regions in healthy controls and patients with early-onset Alzheimer's disease (EOAD), late-onset Alzheimer's disease (LOAD), progressive supranuclear palsy (PSP), and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-GRN). We identified region in SV2A density among controls and observed disease- and region-specific reductions, with the most severe in FTLD-GRN (up to 59.5%) and EOAD. EOAD showed a 49% reduction in the middle frontal gyrus (MFG), while LOAD had over 30% declines in the inferior frontal gyrus (IFG) and hippocampus (CA1). In PSP, smaller but significant reductions were noted in the hippocampal formation, with the inferior temporal gyrus (ITG) relatively unaffected. A strong positive correlation between SV2A and SYP densities confirmed SV2A's reliability as a synaptic integrity marker. This study supports the use of SV2A PET imaging for early diagnosis and monitoring of neurodegenerative diseases, providing essential data for interpreting in vivo PET results. Further research should explore SV2A as a therapeutic target and validate these findings in larger, longitudinal studies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Parkinson's disease (PD) is a prevalent neurodegenerative disorder, and recent evidence suggests that pathogenesis may be in part mediated by inflammatory processes, the molecular and cellular architectures of which are largely unknown. To identify and characterize selectively vulnerable brain cell populations in PD, we performed single-nucleus transcriptomics and unbiased proteomics to profile the prefrontal cortex from postmortem human brains of six individuals with late-stage PD and six age-matched controls. Analysis of nearly 80,000 nuclei led to the identification of eight major brain cell types, including elevated brain-resident T cells in PD, each with distinct transcriptional changes in agreement with the known genetics of PD. By analyzing Lewy body pathology in the same postmortem brain tissues, we found that α-synuclein pathology was inversely correlated with chaperone expression in excitatory neurons. Examining cell-cell interactions, we found a selective abatement of neuron-astrocyte interactions and enhanced neuroinflammation. Proteomic analyses of the same brains identified synaptic proteins in the prefrontal cortex that were preferentially down-regulated in PD. By comparing this single-cell PD dataset with a published analysis of similar brain regions in Alzheimer's disease (AD), we found no common differentially expressed genes in neurons but identified many shared differentially expressed genes in glial cells, suggesting that the disease etiologies, especially in the context of neuronal vulnerability, in PD and AD are likely distinct.

Engineered biological neural networks are indispensable models for investigation of neural function and dysfunction from the subcellular to the network level. Notably, advanced neuroengineering approaches are of significant interest for their potential to replicate the topological and functional organization of brain networks. In this study, we reverse engineered feedforward neural networks of primary cortical and hippocampal neurons, using a custom-designed multinodal microfluidic device with Tesla valve inspired microtunnels. By interfacing this device with nanoporous microelectrodes, we show that the reverse engineered multinodal neural networks exhibit capacity for both segregated and integrated functional activity, mimicking brain network dynamics. To advocate the broader applicability of our model system, we induced localized perturbations with amyloid beta to study the impact of pathology on network functionality. Additionally, we demonstrate long-term culturing of subregion- and layer specific neurons extracted from the entorhinal cortex and hippocampus of adult Alzheimer's-model mice and rats. Our results thus highlight the potential of our approach for reverse engineering of anatomically relevant multinodal neural networks to study dynamic structure-function relationships in both healthy and pathological conditions., (© 2024. The Author(s).)

Background: Persistent innate and adaptive immune responses in the brain contribute to the progression of Alzheimer's disease (AD). APOE4, the most important genetic risk factor for sporadic AD, encodes apolipoprotein E4, which by itself is a potent modulator of immune response. However, little is known about the immune hub that governs the crosstalk between the nervous and the adaptive immune systems. Transient receptor potential vanilloid type 1 (TRPV1) channel is a ligand-gated, nonselective cation channel with Ca 2+ permeability, which has been proposed as a neuroprotective target in AD., Methods: Using Ca 2+ -sensitive dyes, dynamic changes of Ca 2+ in microglia were measured, including exogenous Ca 2+ uptake and endoplasmic reticulum Ca 2+ release. The mRFP-GFP-tagged LC3 plasmid was expressed in microglia to characterize the role of TRPV1 in the autophagic flux. Transcriptomic analyses and flow cytometry were performed to investigate the effects of APOE4 on brain microglia and T cells from APOE-targeted replacement mice with microglia-specific TRPV1 gene deficiency., Results: Both APOE4 microglia derived from induced pluripotent stem cells of AD patients and APOE4-related tauopathy mouse model showed significantly increased cholesterol biosynthesis and accumulation compared to their APOE3 counterparts. Further, cholesterol dysregulation was associated with persistent activation of microglia and elevation of major histocompatibility complex II-dependent antigen presentation in microglia, subsequently accompanied by T cell infiltration. In addition, TRPV1-mediated transient Ca 2+ influx mitigated cholesterol biosynthesis in microglia by suppressing the transcriptional activation of sterol regulatory element-binding protein 2, promoted autophagic activity and reduced lysosomal cholesterol accumulation, which were sufficient to resolve excessive immune response and neurodegeneration in APOE4-related tauopathy mouse model. Moreover, microglia-specific deficiency of TRPV1 gene accelerated glial inflammation, T cell response and associated neurodegeneration in an APOE4-related tauopathy mouse model., Conclusions: The findings provide new perspectives for the treatment of APOE4-dependent neurodegeneration including AD., (© 2024. The Author(s).)

Mass spectrometry-based methods can provide a global expression profile and structural readout of proteins in complex systems. Preserving the in vivo conformation of proteins in their innate state is challenging during proteomic experiments. Here, we introduce a whole animal in vivo protein footprinting method using perfusion of reagents to add dimethyl labels to exposed lysine residues on intact proteins which provides information about protein conformation. When this approach is used to measure dynamic structural changes during Alzheimer's disease (AD) progression in a mouse model, we detect 433 proteins that undergo structural changes attributed to AD, independent of aging, across 7 tissues. We identify structural changes of co-expressed proteins and link the communities of these proteins to their biological functions. Our findings show that structural alterations of proteins precede changes in expression, thereby demonstrating the value of in vivo protein conformation measurement. Our method represents a strategy for untangling mechanisms of proteostasis dysfunction caused by protein misfolding. In vivo whole-animal footprinting should have broad applicability for discovering conformational changes in systemic diseases and for the design of therapeutic interventions., (© 2024. The Author(s).)

The unsatisfactory treatment outcome of Alzheimer's disease (AD) can be attributed to two primary factors, the intricate pathogenic mechanisms leading to restricted treatment effectiveness against single targets and the hindered drug accumulation in brain due to blood-brain barrier obstruction. Therefore, we developed a carrier-free nanomodulator (NanoDS) through the self-assembly of donepezil and simvastatin for direct nose-to-brain delivery. This approach facilitated a rapid and efficient traversal through the nasal epithelial barrier, enabling subsequent drug release and achieving multiple therapeutic effects. Among them, donepezil effectively ameliorated the symptoms of AD and restored synaptic plasticity. Simvastatin exerted a neurotrophic effect and facilitated the clearance of amyloid-β aggregation. At the same time, NanoDS demonstrated effective anti-inflammatory and antioxidative stress effects. This therapy for AD is approached from both symptomatic and etiological perspectives. In the treatment of FAD 4T transgenic mice, it highly improved spatial memory impairment and cognitive deficits while restoring the homeostasis of brain microenvironment. Collectively, our study presented a paradigm for both achieving efficient brain delivery and offering pleiotropic therapies for AD.

Alzheimer's disease (AD) affects millions of people worldwide and represents the most prevalent form of dementia. Treatment strategies aiming to interfere with the formation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs), the two major AD hallmarks, have shown modest or no effect. Recent evidence suggests that ferroptosis, a type of programmed cell death caused by iron accumulation and lipid peroxidation, contributes to AD pathogenesis. The existing link between ferroptosis and AD has been largely based on cell culture and animal studies, while evidence from human brain tissue is limited. Here we evaluate if Aβ is associated with ferroptosis pathways in post-mortem human brain tissue and whether ferroptosis inhibition could attenuate Aβ-related effects in human brain organoids. Performing positive pixel density scoring on immunohistochemically stained post-mortem Brodmann Area 17 sections revealed that the progression of AD pathology was accompanied by decreased expression of nuclear receptor co-activator 4 and glutathione peroxidase 4 in the grey matter. Differentiating between white and grey matter, allowed for a more precise understanding of the disease's impact on different brain regions. In addition, ferroptosis inhibition prevented Aβ pathology, decreased lipid peroxidation and restored iron storage in human AD iPSCs-derived brain cortical organoids at day 50 of differentiation. Differential gene expression analysis of RNAseq of AD organoids compared to isogenic controls indicated activation of the ferroptotic pathway. This was also supported by results from untargeted proteomic analysis revealing significant changes between AD and isogenic brain organoids. Determining the causality between the development of Aβ plaques and the deregulation of molecular pathways involved in ferroptosis is crucial for developing potential therapeutic interventions., (© 2024. The Author(s).)