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Background Toxoplasma gondii infection of Alzheimer's disease model mice decreases amyloid β plaques. We aimed to determine if there is a brain regional difference in amyloid β reduction in the brains of T. gondii- infected compared to control mice. Method Three-month-old 5xFAD (AD model) mice were injected with T. gondii or with phosphate-buffered saline as a control. Intact brains were harvested at 6 weeks postinfection, optically cleared using iDISCO+, and brain-wide amyloid burden was visualized using volumetric light-sheet imaging. Amyloid signal was quantified across each brain and computationally mapped to the Allen Institute Brain Reference Atlas to determine amyloid density in each region. Results A brain-wide analysis of amyloid in control and T. gondii- infected 5xFAD mice revealed that T. gondii infection decreased amyloid burden in the brain globally as well as in the cortex and hippocampus, and many daughter regions. Daughter regions that showed reduced amyloid burden included the prelimbic cortex, visual cortex, and retrosplenial cortex. The olfactory tubercle, a region known to have increased monocytes following T. gondii infection, also showed reduced amyloid after infection. Conclusions T. gondii infection of AD mice reduces amyloid burden in a brain region-specific manner that overlaps with known regions of T. gondii infection and peripheral immune cell infiltration. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Phytocannabinoids inhibit the aggregation and neurotoxicity of the neurotoxic Alzheimer's disease protein β amyloid (Aβ). We characterised the capacity of five proprietary medical cannabis extracts, heated and non‐heated, with varying ratios of cannabidiol and Δ9‐tetrahydrocannabinol and their parent carboxylated compounds to protect against lipid peroxidation and Aβ‐evoked neurotoxicity in PC12 cells.Neuroprotection against lipid peroxidation and Aβ1–42‐induced cytotoxicity was assessed using the thiazolyl blue tetrazolium bromide (MTT) assay. Transmission electron microscopy was used to visualise phytocannabinoid effects on Aβ1–42 aggregation and fluorescence microscopy.Tetrahydrocannabinol (THC)/tetrahydrocannabinolic acid (THCA)‐predominant cannabis extracts demonstrated the most significant overall neuroprotection against Aβ1–42‐induced loss of PC12 cell viability. These protective effects were still significant after heating of extracts, while none of the extracts provided significant neuroprotection to lipid peroxidation via tbhp exposure. Modest inhibition of Aβ1–42 aggregation was demonstrated only with the non‐heated BC‐401 cannabis extract, but overall, there was no clear correlation between effects on fibrils and conferral of neuroprotection.These findings highlight the variable neuroprotective activity of cannabis extracts containing major phytocannabinoids THC/THCA and cannabidiol (CBD)/cannabidiolic acid (CBDA) on Aβ‐evoked neurotoxicity and inhibition of amyloid β aggregation. This may inform the future use of medicinal cannabis formulations in the treatment of Alzheimer's disease and dementia. [ABSTRACT FROM AUTHOR]

The amyloid cascade hypothesis postulates that extracellular deposits of amyloid β (Aβ) are the primary and initial cause leading to the full development of Alzheimer's disease (AD) with intracellular neurofibrillary tangles; however, the details of this mechanism have not been fully described until now. Our preliminary data, coming from our day-to-day neuropathology practice, show that the primary location of the hyperphosphorylated tau protein is in the vicinity of the cell membrane of dystrophic neurites. This observation inspired us to formulate a hypothesis that presumes an interaction between low-density lipoprotein receptor-related protein 1 (LRP1) and fibrillar aggregates of, particularly, Aβ42 anchored at the periphery of neuritic plaques, making internalization of the LRP1-Aβ42 complex infeasible and, thus, causing membrane dysfunction, leading to the tauopathy characterized by intracellular accumulation and hyperphosphorylation of the tau protein. Understanding AD as a membrane dysfunction tauopathy may draw attention to new treatment approaches not only targeting Aβ42 production but also, perhaps paradoxically, preventing the formation of LRP1-Aβ42. [ABSTRACT FROM AUTHOR]

Mild Cognitive Impairment (MCI) is a neurological condition characterized by a noticeable decline in cognitive abilities that falls between normal aging and dementia. Along with some biomarkers like GAP-43, Aβ, tau, and P-tau, brain activity and connectivity are ascribed to MCI; however, the link between brain connectivity changes and such biomarkers in MCI is still being investigated. This study explores the relationship between biomarkers like GAP-43, Aβ, tau, and P-tau, and brain connectivity. We enrolled 25 Participants with normal cognitive function and 23 patients with MCI. Levels of GAP-43, Aβ1–42, t-tau, and p-tau181p in the CSF were measured, and functional connectivity measures including ROI-to-voxel (RV) correlations and the DMN RV-ratio were extracted from the resting-state fMRI data. P-values below 0.05 were considered significant. The results showed that in CN individuals, higher connectivity within the both anterior default mode network (aDMN) and posterior DMN (pDMN) was associated with higher levels of the biomarker GAP-43. In contrast, MCI individuals showed significant negative correlations between DMN connectivity and levels of tau and P-tau. Notably, no significant correlations were found between Aβ levels and connectivity measures in either group. These findings suggest that elevated levels of GAP-43 indicate increased functional connectivity in aDMN and pDMN. Conversely, elevated levels of tau and p-tau can disrupt connectivity through various mechanisms. Thus, the accumulation of tau and p-tau can lead to impaired neuronal connectivity, contributing to cognitive decline. [ABSTRACT FROM AUTHOR]

Amyloid β peptide (Aβ) aggregation and deposition are considered the main causes of Alzheimer's disease. In a previous study, we demonstrated that anionic Zn-phthalocyanine (ZnPc) can interact with the Aβ peptide and inhibit the fibril-formation process. However, due to the inability of anionic ZnPc to cross the intact blood–brain barrier, we decided to explore the interaction of cationic methylated Zn-phthalocyanine (cZnPc) with the peptide. Using a ThT fluorescence assay, we observed that cZnPc dose-dependently and time-dependently inhibited Aβ1-42 fibril levels under in vitro fibril-formation conditions. Electron microscopy revealed that it caused Aβ1-42 peptides to form small aggregates. Western blotting and dot immunoblot oligomer experiments demonstrated that cZnPc increased rather than decreased the levels of oligomers from the very early stages of incubation. A binding assay confirmed that cZnPc could bind with the peptide. Docking simulations indicated that the oligomer species of Aβ1-42 had a higher ability to interact with cZnPc. ANS fluorescence assay results indicated that cZnPc did not affect the hydrophobicity of the peptide. However, cZnPc significantly increased intrinsic tyrosine fluorescence of the peptide after 8 h of incubation in fibril-formation conditions. Importantly, cell culture experiments demonstrated that cZnPc did not exhibit any toxicity up to a concentration of 10 µM. Instead, it protected a neuronal cell line from Aβ1-42-induced toxicity. Thus, our results suggest that cZnPc can affect the aggregation process of Aβ1-42, rendering it non-toxic, which could be crucial for the therapy of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder associated with age. A wealth of evidence indicates that the amyloid β (Aβ) aggregates result from dyshomeostasis between Aβ production and clearance, which plays a pivotal role in the pathogenesis of AD. Consequently, therapies targeting Aβ reduction represent a promising strategy for AD intervention. Tetramethylpyrazine nitrone (TBN) is a novel tetramethylpyrazine derivative with potential for the treatment of AD. Previously, we demonstrated that TBN markedly enhanced cognitive functions and decreased the levels of Aβ, APP, BACE 1, and hyperphosphorylated tau in 3×Tg-AD mice. However, the mechanism by which TBN inhibits Aβ deposition is still unclear. In this study, we employed APP/PS1 mice treated with TBN (60 mg/kg, ig, bid) for six months, and N2a/APP695swe cells treated with TBN (300 μM) to explore the mechanism of TBN in Aβ reduction. Our results indicate that TBN significantly alleviated cognitive impairment and reduced Aβ deposition in APP/PS1 mice. Further investigation of the underlying mechanisms revealed that TBN decreased the expression of APP and BACE1, activated the AMPK/mTOR/ULK1 autophagy pathway, inhibited the PI3K/AKT/mTOR/ULK1 autophagy pathway, and decreased the phosphorylation levels of JNK and ERK in APP/PS1 mice. Moreover, TBN was found to significantly reduce the mRNA levels of APP and BACE1, as well as those of SP1, CTCF, TGF-β, and NF-κB, transcription factors involved in regulating gene expression. Additionally, TBN was observed to decrease the level of miR-346 and increase the levels of miR-147 and miR-106a in the N2a/APP695swe cells. These findings indicate that TBN may reduce Aβ levels likely by reducing APP expression by regulating APP gene transcriptional factors and miRNAs, reducing BACE1 expression, and promoting autophagy activities. [ABSTRACT FROM AUTHOR]

With the rapid progress in deciphering the pathogenesis of Alzheimer's disease (AD), it has been widely accepted that the accumulation of misfolded amyloid β (Aβ) in the brain could cause the neurodegeneration in AD. Although much evidence demonstrates the neurotoxicity of Aβ, the role of Aβ in the nervous system are complex. However, more comprehensive studies are needed to understand the physiological effect of Aβ40 monomers in depth. To explore the physiological mechanism of Aβ, we employed mass spectrometry to investigate the altered proteomic events induced by a lower submicromolar concentration of Aβ. Human neuroblastoma SH-SY5Y cells were exposed to five different concentrations of Aβ1-40 monomers and collected at four time points. The proteomic analysis revealed the time–course behavior of proteins involved in biological processes, such as RNA splicing, nuclear transport and protein localization. Further biological studies indicated that Aβ40 monomers may activate PI3K/AKT signaling to regulate p-Tau, Ezrin and MAP2. These three proteins are associated with dendritic morphogenesis, neuronal polarity, synaptogenesis, axon establishment and axon elongation. Moreover, Aβ40 monomers may regulate their physiological forms by inhibiting the expression of BACE1 and APP via activation of the ERK1/2 pathway. A comprehensive exploration of pathological and physiological mechanisms of Aβ is beneficial for exploring novel treatment. [ABSTRACT FROM AUTHOR]

INTRODUCTION: More robust non‐human primate models of Alzheimer's disease (AD) will provide new opportunities to better understand the pathogenesis and progression of AD. METHODS: We designed a CRISPR/Cas9 system to achieve precise genomic deletion of exon 9 in cynomolgus monkeys using two guide RNAs targeting the 3′ and 5′ intron sequences of PSEN1 exon 9. We performed biochemical, transcriptome, proteome, and biomarker analyses to characterize the cellular and molecular dysregulations of this non‐human primate model. RESULTS: We observed early changes of AD‐related pathological proteins (cerebrospinal fluid Aβ42 and phosphorylated tau) in PSEN1 mutant (ie, PSEN1‐ΔE9) monkeys. Blood transcriptome and proteome profiling revealed early changes in inflammatory and immune molecules in juvenile PSEN1‐ΔE9 cynomolgus monkeys. DISCUSSION: PSEN1 mutant cynomolgus monkeys recapitulate AD‐related pathological protein changes, and reveal early alterations in blood immune signaling. Thus, this model might mimic AD‐associated pathogenesis and has potential utility for developing early diagnostic and therapeutic interventions. Highlights: A dual‐guide CRISPR/Cas9 system successfully mimics AD PSEN1‐ΔE9 mutation by genomic excision of exon 9.PSEN1 mutant cynomolgus monkey‐derived fibroblasts exhibit disrupted PSEN1 endoproteolysis and increased Aβ secretion.Blood transcriptome and proteome profiling implicate early inflammatory and immune molecular dysregulation in juvenile PSEN1 mutant cynomolgus monkeys.Cerebrospinal fluid from juvenile PSEN1 mutant monkeys recapitulates early changes of AD‐related pathological proteins (increased Aβ42 and phosphorylated tau). [ABSTRACT FROM AUTHOR]

Protein aggregation is invariably associated with the inflammation as a factor in Alzheimer's disease (AD). We investigated the interaction between downstream factors of endoplasmic reticulum (ER) stress pathway and inflammation, with implications in cognitive impairment in AD. Amyloid-β (Aβ)(1–42) was administered by bilateral intracerebroventricular (icv) injection in the brain of adult male Wistar rats to experimentally develop AD. The cognitive impairment was assessed by measuring behavioral parameters such as Morris water maze and novel object recognition tests. Levels of pro-inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α and anti-inflammatory cytokines IL-4 and IL-10 were measured by the enzyme-linked immunosorbent assay (ELISA) in different rat brain regions. Inflammatory marker proteins such as cyclo-oxygenase (COX)-2 and phosphorylation of nuclear factor kappa B (NF-КB) (p65) were measured by the western blotting. Gene expression of ER stress downstream factors such as ATF-4, CHOP, and GADD-34 was analyzed by qRT-PCR. Histological studies were performed to check Aβ accumulation and neuronal degeneration. Integrated stress response inhibitor (ISRIB) was used to confirm the specific role of ER stress–mediated inflammation in cognitive impairment. Administration of Aβ(1–42) resulted in alteration in levels of inflammatory cytokines, inflammatory proteins, and mRNA levels of ER stress downstream factors. ISRIB treatment resulted in attenuation of Aβ(1–42)-induced ER stress, inflammation, neurodegeneration, and cognitive impairment in rats. These results indicate that ER stress–mediated inflammation potentiates the cognitive impairment in AD. An understanding of cascade of events, interaction of ER stress which was a hallmark of the present investigation together with inflammation and modulation of downstream signalling factors could serve as potent biomarkers to study AD progression. Schematic representation of interaction between ER stress and inflammation. Administration of Aβ(1–42) resulted in ER stress which caused the activation of factors of PERK pathway, inflammation, neuronal degeneration, and cognitive impairment. ISRIB treatment caused downregulation of ATF-4 and attenuation of inflammation indicating a role of ER stress–mediated inflammation in the cognitive impairment in AD. The site of action of ISRIB is shown in blue color [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder which is characterized by cognitive deficits and abnormal memory formation. Histone acetylation is essential for hippocampal memory formation and improving the cognitive deficits, and histone deacetylase 2 (HDAC2) is increased in the hippocampus of AD patients. The present study evaluated the effects of the nitric oxide (NO) mimetics, L-arginine and the nitrosothiol NO donor, s-nitrosoglutathione (GSNO), on memory and brain HDAC2 levels in experimental animal model of sporadic Alzheimer's disease (sAD). AD was induced experimentally in rats by intracerebroventricular injection of streptozotocin (STZ, 3mg/kg). The effects of NO mimetics, GSNO and L-arginine, were assessed on STZ induced cognitive deficits in the Morris water maze (MWM) test, and, following this, the hippocampal homogenates were assayed for amyloid-β, brain derived neurotropic factor (BDNF) and HDAC2 levels. The neurobehavioral and biochemical data of the drug treated groups were compared with those of experimental control group. The results showed that icv-STZ induced cognitive deficits were differentially attenuated by GSNO (50µg/kg) and, to a lesser extent, L-arginine (100mg/kg) with improvement in the spatial learning tasks in MWM test. These behavioral changes were associated with decreased levels of biochemical markers viz. amyloid β, BDNF and HDAC2 levels in hippocampus. It is inferred that NO donors like GSNO could influence AD pathophysiology via epigenetic modification of HDAC2 inhibition. [ABSTRACT FROM AUTHOR]

Background: Caloric restriction (CR) might be effective for alleviating/preventing Alzheimer's disease (AD), but the biological mechanisms remain unclear. In the current study, we explored whether CR caused an alteration of gut microbiome and resulted in the attenuation of cognitive impairment of AD animal model. Methods: Thirty‐week‐old male APP/PS1 transgenic mice were used as AD models (AD mouse). CR was achieved by 30% reduction of daily free feeding (ad libitum, AL) amount. The mice were fed with CR protocol or AL protocol for six consecutive weeks. Results: We found that with CR treatment, AD mice showed improved ability of learning and spatial memory, and lower levels of Aβ40, Aβ42, IL‐1β, TNF‐α, and ROS in the brain. By sequencing 16S rDNA, we found that CR treatment resulted in significant diversity in composition and abundance of gut flora. At the phylum level, Deferribacteres (0.04%), Patescibacteria (0.14%), Tenericutes (0.03%), and Verrucomicrobia (0.5%) were significantly decreased in CR‐treated AD mice; at the genus level, Dubosiella (10.04%), Faecalibaculum (0.04%), and Coriobacteriaceae UCG‐002 (0.01%) were significantly increased in CR‐treated AD mice by comparing with AL diet. Conclusions: Our results demonstrate that the attenuation of AD following CR treatment in APP/PS1 mice may result from alterations in the gut microbiome. Thus, gut flora could be a new target for AD prevention and therapy. [ABSTRACT FROM AUTHOR]

Abstract Mild Cognitive Impairment (MCI) is a neurological condition characterized by a noticeable decline in cognitive abilities that falls between normal aging and dementia. Along with some biomarkers like GAP-43, Aβ, tau, and P-tau, brain activity and connectivity are ascribed to MCI; however, the link between brain connectivity changes and such biomarkers in MCI is still being investigated. This study explores the relationship between biomarkers like GAP-43, Aβ, tau, and P-tau, and brain connectivity. We enrolled 25 Participants with normal cognitive function and 23 patients with MCI. Levels of GAP-43, Aβ1–42, t-tau, and p-tau181p in the CSF were measured, and functional connectivity measures including ROI-to-voxel (RV) correlations and the DMN RV-ratio were extracted from the resting-state fMRI data. P-values below 0.05 were considered significant. The results showed that in CN individuals, higher connectivity within the both anterior default mode network (aDMN) and posterior DMN (pDMN) was associated with higher levels of the biomarker GAP-43. In contrast, MCI individuals showed significant negative correlations between DMN connectivity and levels of tau and P-tau. Notably, no significant correlations were found between Aβ levels and connectivity measures in either group. These findings suggest that elevated levels of GAP-43 indicate increased functional connectivity in aDMN and pDMN. Conversely, elevated levels of tau and p-tau can disrupt connectivity through various mechanisms. Thus, the accumulation of tau and p-tau can lead to impaired neuronal connectivity, contributing to cognitive decline.

• House dust mite exposure-induced asthma potentiated Aβ plaque load in AppNL-G-F mice. • Asthma increased astrogliosis and microgliosis in AppNL-G-F mice. • Asthma altered brain cytokine levels and vascular integrity in AppNL-G-F mice. Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques, neuroinflammation, and neuronal death. Besides aging, various comorbidities increase the risk of AD, including obesity, diabetes, and allergic asthma. Epidemiological studies have reported a 2.17-fold higher risk of dementia in asthmatic patients. However, the molecular mechanism(s) underlying this asthma-associated AD exacerbation is unknown. This study was designed to explore house dust mite (HDM)-induced asthma effects on AD-related brain changes using the AppNL-G-F transgenic mouse model of disease. Male and female 8–9 months old C57BL/6J wild type and AppNL-G-F mice were exposed to no treatment, saline sham, or HDM extract every alternate day for 16 weeks for comparison across genotypes and treatment. Mice were euthanized at the end of the experiment, and broncho-alveolar lavage fluid (BALF), blood, lungs, and brains were collected. BALF was used to quantify immune cell phenotype, cytokine levels, total protein content, lactate dehydrogenase (LDH) activity, and total IgE. Lungs were sectioned and stained with hematoxylin and eosin, Alcian blue, and Masson's trichrome. Serum levels of cytokines and soluble Aβ1-40/42 were quantified. Brains were sectioned and immunostained for Aβ, GFAP, CD68, and collagen IV. Finally, frozen hippocampi and temporal cortices were used to perform Aβ ELISAs and cytokine arrays, respectively. HDM exposure led to increased levels of inflammatory cells, cytokines, total protein content, LDH activity, and total IgE in the BALF, as well as increased pulmonary mucus and collagen staining in both sexes and genotypes. Levels of serum cytokines increased in all HDM-exposed groups. Serum from the AppNL-G-F HDM-induced asthma group also had significantly increased soluble Aβ1-42 levels in both sexes. In agreement with this peripheral change, hippocampi from asthma-induced male and female AppNL-G-F mice demonstrated elevated Aβ plaque load and increased soluble Aβ 1–40/42 and insoluble Aβ 1–40 levels. HDM exposure also increased astrogliosis and microgliosis in both sexes of AppNL-G-F mice, as indicated by GFAP and CD68 immunoreactivity, respectively. Additionally, HDM exposure elevated cortical levels of several cytokines in both sexes and genotypes. Finally, HDM-exposed groups also showed a disturbed blood–brain-barrier (BBB) integrity in the hippocampus of AppNL-G-F mice, as indicated by decreased collagen IV immunoreactivity. HDM exposure was responsible for an asthma-like condition in the lungs that exacerbated Aβ pathology, astrogliosis, microgliosis, and cytokine changes in the brains of male and female AppNL-G-F mice that correlated with reduced BBB integrity. Defining mechanisms of asthma effects on the brain may identify novel therapeutic targets for asthma and AD. [ABSTRACT FROM AUTHOR]

Loss of proteostasis is a highly conserved feature of aging across model organisms and results in the accumulation of insoluble protein aggregates. Protein insolubility is also a unifying feature of major age-related neurodegenerative diseases, including Alzheimer's Disease (AD), in which hundreds of insoluble proteins associate with aggregated amyloid beta (Aβ) in senile plaques. Despite the connection between aging and AD risk, therapeutic approaches to date have overlooked aging-driven generalized protein insolubility as a contributing factor. However, proteins that become insoluble during aging in model organisms are capable of accelerating Aβ aggregation in vitro and lifespan in vivo. Here, using an unbiased proteomics approach, we questioned the relationship between Aβ and age-related protein insolubility. Specifically, we uncovered that Aβ expression drives proteome-wide protein insolubility in C. elegans, even in young animals, and this insoluble proteome is highly similar to the insoluble proteome driven by normal aging, this vulnerable sub-proteome we term the core insoluble proteome (CIP). We show that the CIP is enriched with proteins that modify Aβ toxicity in vivo, suggesting the possibility of a vicious feedforward cycle in the context of AD. Importantly, using human genome-wide association studies (GWAS), we show that the CIP is replete with biological processes implicated not only in neurodegenerative diseases but also across a broad array of chronic, age-related diseases (CARDs). This provides suggestive evidence that age-related loss of proteostasis could play a role in general CARD risk. Finally, we show that the geroprotective, gut-derived metabolite, Urolithin A, relieves Aβ toxicity, supporting its use in clinical trials for dementia and age-related diseases. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by the abnormal aggregation of amyloid β (Aβ) peptide in extracellular deposits generated upon proteolysis of Amyloid Precursor Protein (APP). While copper (Cu(II)) binds to Aβ in soluble oligomeric and aggregated forms, its interaction with membrane‐bound Aβ remains elusive. Investigating these interactions is crucial for understanding AD pathogenesis. Here, utilizing SDS micelles as a simplified membrane mimic, we focus on elucidating the interplay between membrane‐anchored Aβ and copper, given their pivotal roles in AD. We employed spectroscopic techniques including UV, CD, and EPR to characterize the active site of Cu‐Aβ complexes. Our findings demonstrate that copper interacts with Aβ peptides in membrane‐mimicking micellar environments similarly to aqueous buffer solutions. Cu‐Aβ complexes in this medium also induce higher hydrogen peroxide (H2O2) production, potentially contributing to AD‐related oxidative stress. Moreover, we observe an increased oxidation rate of neurotransmitter such as dopamine by Cu‐Aβ complexes. These results enhance our understanding of Cu‐Aβ interactions in AD pathology and offer insights into potential therapeutic interventions targeting this interaction. [ABSTRACT FROM AUTHOR]

Aurora kinase A (AURKA) is a serine/threonine-protein kinase that regulates microtubule organization during neuron migration and neurite formation. Decreased activity of AURKA was found in Alzheimer's disease (AD) brain samples, but little is known about the role of AURKA in AD pathogenesis. Here, we demonstrate that AURKA is expressed in primary cultured rat neurons, neurons from adult mouse brains, and neurons in postmortem human AD brains. AURKA phosphorylation, which positively correlates with its activity, is reduced in human AD brains. In SH-SY5Y cells, pharmacological activation of AURKA increased AURKA phosphorylation, acidified endolysosomes, decreased the activity of amyloid beta protein (Aβ) generating enzyme β-site amyloid precursor protein cleaving enzyme (BACE-1), increased the activity of the Aβ degrading enzyme cathepsin D, and decreased the intracellular and secreted levels of Aβ. Conversely, pharmacological inhibition of AURKA decreased AURKA phosphorylation, de-acidified endolysosomes, decreased the activity of cathepsin D, and increased intracellular and secreted levels of Aβ. Thus, reduced AURKA activity in AD may contribute to the development of intraneuronal accumulations of Aβ and extracellular amyloid plaque formation. [ABSTRACT FROM AUTHOR]

• Aβ42-hIAPP co-oligomers show 2.3–3.5 times higher toxicity than AβO. • Increased apoptosis in glutamatergic neurons exposed to Aβ42-hIAPP. • Aβ42-hIAPP co-oligomers induce more severe AD pathology than AβO. • Novel insights into AD pathogenesis, implicating hIAPP in AD pathology. • Potential for constructing animal models to study Alzheimer's disease. The Aβ hypothesis has long been central to Alzheimer's disease (AD) theory, with a recent surge in attention following drug approvals targeting Aβ plaque clearance. Aβ42 oligomers (AβO) are key neurotoxins. While β-amyloid (Aβ) buildup is a hallmark of AD, postmortem brain analyses have unveiled human islet amyloid polypeptide (hIAPP) deposition in AD patients, suggesting a potential role in Alzheimer's pathology. This study investigates the neurotoxic effects of co-aggregates of Aβ42 and hIAPP, specifically focusing on their impact on cell survival, apoptosis, and AD-like pathology. We analyzed and compared the impact of AβO and Aβ42-hIAPP on cell survival in SH-SY5Y cells, apoptosis and inducing AD-like pathology in glutamatergic neurons. Aβ42-hIAPP co-oligomers exhibited significantly greater toxicity, causing 2.3–3.5 times higher cell death compared to AβO alone. Furthermore, apoptosis rates were significantly exacerbated in glutamatergic neurons when exposed to Aβ42-hIAPP co-oligomers. The study also revealed that Aβ42-hIAPP co-oligomers induced typical AD-like pathology in glutamatergic neurons, including the presence of Aβ deposits (detected by 6E10 and 4G8 immunofluorescence) and alterations in tau protein (changes in total tau HT7, phosphorylated tau AT8, AT180). Notably, Aβ42-hIAPP co-oligomers induced a more severe AD pathology compared to AβO alone. These findings provide compelling evidence for the heightened toxicity of Aβ42-hIAPP co-oligomers on neurons and their role in exacerbating AD pathology. The study contributes novel insights into the pathogenesis of Alzheimer's disease, highlighting the potential involvement of hIAPP in AD pathology. Together, these findings offer novel insights into AD pathogenesis and routes for constructing animal models. [ABSTRACT FROM AUTHOR]

Although studies have demonstrated that genome instability is accumulated in patients with Alzheimer's disease (AD), the specific types of genome instability linked to AD pathogenesis remain poorly understood. Here, we report the first characterization of the age‐ and sex‐related trajectories of telomere length (TL) and micronuclei in APP/PS1 mice model and wild‐type (WT) controls (C57BL/6). TL was measured in brain (prefrontal cortex, cerebellum, pituitary gland, and hippocampus), colon and skin, and MN was measured in bone marrow in 6‐ to 14‐month‐old mice. Variation in TL was attributable to tissue type, age, genotype and, to a lesser extent, sex. Compared to WT, APP/PS1 had a significantly shorter baseline TL across all examined tissues. TL was inversely associated with age in both genotypes and TL shortening was accelerated in brain of APP/PS1. Age‐related increase of micronuclei was observed in both genotypes but was accelerated in APP/PS1. We integrated TL and micronuclei data with data on cognition performance and brain amyloidosis. TL and micronuclei were linearly correlated with cognition performance or Aβ40 and Aβ42 levels in both genotypes but to a greater extent in APP/PS1. These associations in APP/PS1 mice were dominantly driven by females. Together, our findings provide foundational knowledge to infer the TL and micronuclei trajectories in APP/PS1 mice during disease progression, and strongly support that TL attrition and micronucleation are tightly associated with AD pathogenesis in a female‐biased manner. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of amyloid beta (Aβ) plaques in the brain. Aβ1–42 is the main component of Aβ plaque, which is toxic to neuronal cells. Si nanowires (Si NWs) have the advantages of small particle size, high specific surface area, and good biocompatibility, and have potential application prospects in suppressing Aβ aggregation. In this study, we employed the vapor–liquid–solid (VLS) growth mechanism to grow Si NWs using Au nanoparticles as catalysts in a plasma-enhanced chemical vapor deposition (PECVD) system. Subsequently, these Si NWs were transferred to a phosphoric acid buffer solution (PBS). We found that Si NWs significantly reduced cell death in PC12 cells (rat adrenal pheochromocytoma cells) induced by Aβ1–42 oligomers via double staining with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and fluorescein diacetate/propyl iodide (FDA/PI). Most importantly, pre-incubated Si NWs largely prevented Aβ1–42 oligomer-induced PC12 cell death, suggesting that Si NWs exerts an anti-Aβ neuroprotective effect by inhibiting Aβ aggregation. The analysis of Fourier Transform Infrared (FTIR) results demonstrates that Si NWs reduce the toxicity of fibrils and oligomers by intervening in the formation of β-sheet structures, thereby protecting the viability of nerve cells. Our findings suggest that Si NWs may be a potential therapeutic agent for AD by protecting neuronal cells from the toxicity of Aβ1–42. [ABSTRACT FROM AUTHOR]

Amyloid β (Aβ) is a central contributor to neuronal damage and cognitive impairment in Alzheimer's disease (AD). Aβ disrupts AMPA receptor-mediated synaptic plasticity, a key factor in early AD progression. Numerous studies propose that Aβ oligomers hinder synaptic plasticity, particularly long-term potentiation (LTP), by disrupting GluA1 (encoded by GRIA1) function, although the precise mechanism remains unclear. In this study, we demonstrate that Aβ mediates the accumulation of GM1 ganglioside in lipid raft domains of cultured cells, and GluA1 exhibits preferential localization in lipid rafts via direct binding to GM1. Aβ enhances the raft localization of GluA1 by increasing GM1 in these areas. Additionally, chemical LTP stimulation induces lipid raft-dependent GluA1 internalization in Aβ-treated neurons, resulting in reduced cell surface and postsynaptic expression of GluA1. Consistent with this, disrupting lipid rafts and GluA1 localization in rafts rescues Aβ-mediated suppression of hippocampal LTP. These findings unveil a novel functional deficit in GluA1 traffickingAmyloid β (Aβ) is a central contributor to neuronal damage and cognitive impairment in Alzheimer's disease (AD). Aβ disrupts AMPA receptor-mediated synaptic plasticity, a key factor in early AD progression. Numerous studies propose that Aβ oligomers hinder synaptic plasticity, particularly long-term potentiation (LTP), by disrupting GluA1 (encoded by GRIA1) function, although the precise mechanism remains unclear. In this study, we demonstrate that Aβ mediates the accumulation of GM1 ganglioside in lipid raft domains of cultured cells, and GluA1 exhibits preferential localization in lipid rafts via direct binding to GM1. Aβ enhances the raft localization of GluA1 by increasing GM1 in these areas. Additionally, chemical LTP stimulation induces lipid raft-dependent GluA1 internalization in Aβ-treated neurons, resulting in reduced cell surface and postsynaptic expression of GluA1. Consistent with this, disrupting lipid rafts and GluA1 localization in rafts rescues Aβ-mediated suppression of hippocampal LTP. These findings unveil a novel functional deficit in GluA1 trafficking induced by Aβ, providing new insights into the mechanism underlying AD-associated cognitive dysfunction. induced by Aβ, providing new insights into the mechanism underlying AD-associated cognitive dysfunction. [ABSTRACT FROM AUTHOR]

Both the endothelial (eNOS) and the neuronal (nNOS) isoforms of constitutive Nitric Oxide Synthase have been implicated in vascular dysfunctions in Alzheimer's disease (AD). We aimed to explore the relationship between amyloid pathology and NO dynamics by comparing the cerebrospinal fluid (CSF) levels of nNOS and eNOS of 8 healthy controls (HC) and 27 patients with a clinical diagnosis of Alzheimer's disease and isolated CSF amyloid changes, stratified according to APOE ε genotype (APOE ε3 = 13, APOE ε4 = 14). Moreover, we explored the associations between NOS isoforms, CSF AD biomarkers, age, sex, cognitive decline, and blood–brain barrier permeability. In our cohort, both eNOS and nNOS levels were increased in APOE ε3 with respect to HC and APOE ε4. CSF eNOS inversely correlated with CSF Amyloid-β42 selectively in carriers of APOE ε3; CSF nNOS was negatively associated with age and CSF p-tau only in the APOE ε4 subgroup. Increased eNOS could represent compensative vasodilation to face progressive Aβ-induced vasoconstriction in APOE ε3, while nNOS could represent the activation of NO-mediated plasticity strategies in the same group. Our results confirm previous findings that the APOE genotype is linked with different vascular responses to AD pathology. [ABSTRACT FROM AUTHOR]

Amyloid β (Aβ) is pivotal in the progression of Alzheimer’s disease (AD) by inducing neuron damage. Recent evidences implied that the formation of mitochondrial permeability transition pore (mPTP) was involved in Aβ-mediated mitochondrial dysfunction. Cyclophilin D (CypD), which is the essential component of mPTP, could interact with Aβ and promote mPTP formation, resulting in severe mitochondrial dysfunction and eventually cell death. In this study, we demonstrated that a glycopeptide, FMP-6-S4, purified from the fruit of Fructus Mori bond to CypD and suppressed its expression. Furthermore, FMP-6-S4 markedly inhibited the opening of mPTP, the generation of reactive oxygen species and calcium releasing. Mechanistically study showed that FMP-6-S4 could bind to CypD to disrupt the interaction between CypD and Aβ42. Finally, FMP-6-S4 could bind to Aβ42 directly then attenuate cell damage induced by Aβ42 via p53-puma signaling pathway. Together, our results suggest FMP-6-S4 might be a potential candidate for anti-AD drug development.

Cerebral amyloid angiopathy (CAA) has been proven to be the most common pathological change in cerebral small vessel disease except arteriosclerosis. In recent years, with the discovery of imaging technology and new imaging markers, the diagnostic rate of CAA has greatly improved. CAA plays an important role in non-hypertensive cerebral hemorrhage and cognitive decline. This review comprehensively describes the etiology, epidemiology, pathophysiological mechanisms, clinical features, imaging manifestations, imaging markers, diagnostic criteria, and treatment of CAA to facilitate its diagnosis and treatment and reduce mortality.

Objectives: The herbs in Tao Hong Si Wu Decoction (THSWD) are beneficial in the treatment of cognitive impairment. However, the underlying mechanisms of THSWD in treating diabetes‐associated cognitive dysfunction (DACD) are not entirely explored. This study is aimed to investigate the therapeutic effects of THSWD in DACD model rats and the underlying mechanism. Methods: Ultra‐high‐phase liquid chromatography was employed to identify the main compounds contained in the THSWD extract. DACD rat model was induced by feeding with a high‐sugar and high‐fat diet and injecting streptozotocin (35 mg/kg). DACD rats were gavaged with THSWD for 1 week. The learning and memory abilities of the rats were measured by using the Morris water maze. Western blotting was used to detect the changes in DACD rat targets. Statistical methods were used to evaluate the correlation between proteins. Results: The results show that THSWD effectively reduced the escape latency, hippocampal neuron damage, glycosylated hemoglobin, type A1C, and blood lipid levels in DACD rats. Furthermore, DACD rats showed significantly increased amyloid precursor protein, β‐secretase, Aβ1−40, Aβ1−42, Tau phosphorylation, and advanced glycation end products (AGEs) expression. However, THSWD treatment can reverse this phenomenon. Conclusions: THSWD can improve the learning and memory abilities of DACD rats by inhibiting the expression of AEGs‐AGE receptors pathway, which provides an experimental basis for the clinical application of THSWD. In addition, the experiment combines pharmacological and statistical methods, which offers a new perspective for the study of Chinese herbal medicine. Key points: Tao Hong Si Wu Decoction (THSWD) can improve the learning and memory abilities of diabetes‐associated cognitive dysfunction (DACD) rats.Reduced Aβ content was associated with more favorable cognitive abilities.The advanced glycation end products (AGEs)‐AGE receptors (RAGE) pathway may be a key pathway for THSWD to alleviate symptoms in DACD rats and exert therapeutic effects. [ABSTRACT FROM AUTHOR]

Background: Phytocannabinoids (pCBs) have been shown to inhibit the aggregation and neurotoxicity of the neurotoxic Alzheimer's disease protein beta amyloid (Aβ). We characterized the capacity of six pCBs—cannabichromene (CBC), cannabigerol (CBG), cannabinol (CBN), cannabidivarin (CBDV), cannabidiol (CBD) and Δ9‐tetrahydrocannabinol (Δ9‐THC)—to disrupt Aβ aggregation and protect against Aβ‐evoked neurotoxicity in PC12 cells. Methods: Neuroprotection against lipid peroxidation and Aβ‐induced cytotoxicity was assessed using the MTT assay. Transmission electron microscopy was used to visualize pCB effects on Aβ aggregation and fluorescence microscopy, with morphometrics and principal component analysis to assess PC12 cell morphology. Results: CBD inhibited lipid peroxidation with no significant effect on Aβ toxicity, whilst CBN, CBDV and CBG provided neuroprotection. CBC, CBG and CBN inhibited Aβ1–42‐induced neurotoxicity in PC12 cells, as did Δ9‐THC, CBD and CBDV. CBC, CBN and CBDV inhibited Aβ aggregation, whilst Δ9‐THC reduced aggregate density. Aβ1–42 induced morphological changes in PC12 cells, including a reduction in neuritic projections and rounded cell morphology. CBC and CBG inhibited this effect, whilst Δ9‐THC, CBD and CBDV did not alter Aβ1–42 effects on cell morphology. Conclusions: These findings highlight the neuroprotective activity of CBC, CBG and CBN as novel pCBs associated with variable effects on Aβ‐evoked neurite damage and inhibition of amyloid β aggregation. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We investigated associations of Alzheimer's disease (AD) serum biomarkers with longitudinal changes in cognitive function from mid‐ to late life among women. METHODS: The study population included 192 women with the median age of 53.3 years at baseline, from the Study of Women's Health Across the Nation Michigan Cohort, followed up over 14 years. Associations between baseline serum amyloid β (Aβ)42, the Aβ42/40 ratio, phosphorylated tau181 (p‐tau181), and total tau with longitudinal changes in cognition were evaluated using linear mixed effects models. RESULTS: After adjusting for confounders, lower Aβ42/40 ratios were associated with faster declines in the Digit Span Backward Test. Higher p‐tau181 also showed a borderline statistically significant association with more rapid decline in the Symbol Digit Modalities Test. DISCUSSION: Our findings suggest that mid‐life serum AD biomarkers could be associated with accelerated cognitive decline from mid‐ to late life in women. Future studies with larger samples are needed to validate and extend our findings. Highlights: This study investigates midlife serum AD biomarkers on longitudinal cognitive function changes in women.Mid‐life serum AD biomarkers are associated with accelerated cognitive decline.A decrease in the Aβ42/40 ratio was associated with a faster decline in the DSB score.A higher p‐tau181 concentration was associated with a faster decline in the SDMT score. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by aggregation of amyloid beta (Aβ) plaque. RhoA may serve as a potential target for prevention against AD given its role in the amyloidogenic pathway. The recent emergence of the gut-brain axis has linked lactic acid bacteria (LAB) to neuroprotection against AD. This study assessed the importance of RhoA inhibition in mediating the neuroprotective potential of LAB. To this end, de Man, Rogosa and Sharpe (MRS) broth fermented by lactobacilli or pediococci were tested against SK-N-SH (a human neuroblastoma cell line) in the presence of RhoA activator II for 24 h after which the RhoA activity was measured using the G-LISA Kit. Fluorescence staining of f-actin stress fibres was performed to validate RhoA inhibition. SK-N-SH was transfected with plasmid expressing amyloid precursor protein (APP) gene. The Aβ concentration in transfected cells exposed to LAB-derived cell free supernatant (CFS) in the presence of RhoA activator II was measured using the ELISA kit. Furthermore, this study measured organic acids in LAB-derived CFS using the gas chromatography. It was found that LAB-derived CFS yielded strain-dependent inhibition of RhoA, with LAB6- and LAB12-derived CFS being the most potent Pediococcal- and Lactiplantibacillus-based RhoA inhibitor, respectively. Lesser stress fibres were formed under treatment with LAB-derived CFS. The LAB-derived CFS also significantly inhibited Aβ in SK-N-SH transfected with APP gene in the presence of RhoA activator II. The LAB-derived CFS was presented with increased lactic acid, acetic acid, butyric acid and propionic acid. The present findings warrant in-depth study using animal models. [ABSTRACT FROM AUTHOR]

Activation of glial cells, astrocytes and microglia, has been observed in neurodegenerative diseases including Alzheimer's disease (AD). Amyloid β (Aβ), which is aggregated and the aggregation is detected as characteristic pathology in AD brain, is known to be produced by neurons and to activate glial cells. Clearance of Aβ from the brain via active transport system is important to prevent the accumulation and aggregation. Low density lipoprotein receptor-related protein 2 (LRP2/megalin) is an Aβ transporter. However, expression and contribution of LRP2 in astrocytes and microglia remain to be clarified. In the present study, we examined the expression of LRP2 and its roles in cultured astrocytes prepared from rat embryonic brain cortex and mouse microglial cell line BV-2. Both cultured rat astrocytes and BV-2 cells expressed LRP2 mRNA detected by RT-PCR. When lipopolysaccharide (LPS) or all-trans retinoic acid (ATRA) were added to BV-2 cells, LRP2 mRNA expression and uptake of microbeads, Aβ and insulin were increased. On the other hand, LPS decreased LRP2 expression and uptake of Aβ and insulin in cultured astrocytes. Knockdown of LRP2 using siRNA attenuated the LPS- or ATRA-increased uptake of microbeads, Aβ and insulin in BV-2 cells. These results suggest that LRP2 was expressed in both astrocytes and microglia and might be involved in endocytosis activities. Adequate control of LRP2 expression and function in astrocytes and microglia might regulate Aβ and insulin levels in brain and would be a potential target in AD pathology. [ABSTRACT FROM AUTHOR]

Alzheimer's Disease (AD) is a complex neurodegenerative disease resulting in progressive loss of memory, language and motor abilities caused by cortical and hippocampal degeneration. This review captures the landscape of understanding of AD pathology, diagnostics, and current therapies. Two major mechanisms direct AD pathology: (1) accumulation of amyloid β (Aβ) plaque and (2) tau-derived neurofibrillary tangles (NFT). The most common variants in the Aβ pathway in APP, PSEN1, and PSEN2 are largely responsible for early-onset AD (EOAD), while MAPT, APOE, TREM2 and ABCA7 have a modifying effect on late-onset AD (LOAD). More recent studies implicate chaperone proteins and Aβ degrading proteins in AD. Several tests, such as cognitive function, brain imaging, and cerebral spinal fluid (CSF) and blood tests, are used for AD diagnosis. Additionally, several biomarkers seem to have a unique AD specific combination of expression and could potentially be used in improved, less invasive diagnostics. In addition to genetic perturbations, environmental influences, such as altered gut microbiome signatures, affect AD. Effective AD treatments have been challenging to develop. Currently, there are several FDA approved drugs (cholinesterase inhibitors, Aß-targeting antibodies and an NMDA antagonist) that could mitigate AD rate of decline and symptoms of distress. [ABSTRACT FROM AUTHOR]

Besides COVID‐19, two of the most critical outbreaks of our day are insulin resistance, type 2 diabetes mellitus (T2DM), and Alzheimer's disease (AD). Each disease's pathophysiology is well established. Furthermore, a substantial overlap between them has coexisted. Uncertainty remains on whether T2DM and AD are parallel illnesses with the same origin or separate illnesses linked through violent pathways. The current study was aimed at testing whether the insulin resistance in the brain results in AD symptoms or not. Insulin resistance was induced in the brains of rats using a single intracerebroventricular streptozotocin (STZ) dose. We then measured glucose, insulin receptor substrate 2 (IRS‐2), amyloid β (Aβ) deposition, and tau phosphorylation in the brain to look for signs of insulin resistance and AD. The results of this study indicated that a single dose of STZ was able to induce insulin resistance in the brain and significantly decline IRS‐2. This resistance was accompanied by obvious memory loss, Aβ deposition, and tau phosphorylation, further visible diminishing in neurotransmitters such as dopamine and acetylcholine. Furthermore, oxidative stress was increased due to the antioxidant system being compromised. Interestingly, the pancreas injury and peripheral insulin resistance coexisted with brain insulin resistance. Indeed, the antidiabetic metformin was able to enhance all these drastic effects. In conclusion, brain insulin resistance could lead to AD and vice versa. These are highly linked syndromes that could influence peripheral organs. Further studies are required to stabilize this putative pathobiology relationship between them. [ABSTRACT FROM AUTHOR]

Introduction: Apolipoprotein (apo) E4, being a major genetic risk factor for Alzheimer's disease (AD), is actively involved in the proteolytic processing of amyloid precursor protein (APP) to amyloid β (Aβ) peptide, the principle constituent of amyloid plaques in Alzheimer Disease (AD) patients. ApoE4 is believed to affect APP processing through intracellular cholesterol homeostasis, whereas lowering the cholesterol level by pharmacological agents has been suggested to reduce Aβ production. This study has investigated the effects of hypolipidemic agents fenofibrate, and the flavonoids--naringenin and diosmetin--on apoE4-induced APP processing in rat neuroblastoma cells stably transfected with human wild-type APP 695 (B103-hAPP695wt). Results: B103-hAPP695wt cells were pretreated with different doses of flavonoids and fenofibrate for 1 h prior to apoE4 exposure for 24 h. ApoE4- induced production of intra- and extracellular Aβ peptides has been reduced with fenofibrate, naringenin, and diosmetin treatments. Pretreatment with diosmetin has significantly reduced apoE4-induced full-length APP (fl- APP) expression, whereas naringenin and fenofibrate had no effect on it. In addition, the increase in the apoE4-induced secretion of sAPPtotal and sAPPα has been dose-dependently reduced with drug pretreatment. On the other hand, the decrease in the expression of both APP-carboxy terminal fragments (CTF)-α and --β (generated by the α- or β-secretase cleavage of APP) by apoE4 was dose-dependently increased in cells pretreated with fenofibrate and naringenin but not diosmetin. Conclusion: Thus, we suggest that fenofibrate, naringenin, and diosmetin treatments can reduce apoE4- induced Aβ production by distinct mechanisms that may prove useful in developing drugs for AD patients. [ABSTRACT FROM AUTHOR]

Fluorescent probes are a powerful tool for imaging amyloid β (Aβ) plaques, the hallmark of Alzheimer’s disease (AD). Herein, we report the synthesis and comprehensive characterization of 21 novel probes as well as their optical properties and binding affinities to Aβ fibrils. One of these dyes, 1Ae, exhibited several improvements over FDDNP, an established biomarker for Aβ- and Tau-aggregates. First, 1Ae had large Stokes shifts (138–213 nm) in various solvents, thereby reducing self-absorption. With a high quantum yield ratio (φ(dichloromethane/methanol) = 104), 1Ae also ensures minimal background emission in aqueous environments and high sensitivity. In addition, compound 1Ae exhibited low micromolar binding affinity to Aβ fibrils in vitro (Kd = 1.603 µM), while increasing fluorescence emission (106-fold) compared to emission in buffer alone. Importantly, the selective binding of 1Ae to Aβ1–42 fibrils was confirmed by an in cellulo assay, supported by ex vivo fluorescence microscopy of 1Ae on postmortem AD brain sections, allowing unequivocal identification of Aβ plaques. The intermolecular interactions of fluorophores with Aβ were elucidated by docking studies and molecular dynamics simulations. Density functional theory calculations revealed the unique photophysics of these rod-shaped fluorophores, with a twisted intramolecular charge transfer (TICT) excited state. These results provide valuable insights into the future application of such probes as potential diagnostic tools for AD in vitro and ex vivo such as determination of Aβ1–42 in cerebrospinal fluid or blood.

Introduction: Total ginsenosides (TG), the major active constituents of ginseng, have been proven to be beneficial in treatment of Alzheimer’s disease (AD). However, the underlying mechanism of TG remains unclear. Methods: APP/PS1 mice and N2a/APP695 cells were used as in vivo and in vitro model, respectively. Morris water maze (MWM) was used to investigate behavioral changes of mice; neuronal pathological changes were assessed by hematoxylin and eosin (H&E) and nissl staining; immunofluorescence staining was used to examine amyloid beta (Aβ) deposition; Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were used to examine the expression of relative amyloidogenic genes and proteins. Moreover, the antagonist of PPARγ, GW9662, was used to determine whether the effects of TG on Aβ production were associated with PPARγ activity. Results: TG treatment increased the spatial learning and memory abilities of APP/PS1 mice while decreasing the Aβ accumulation in the cortex and hippocampus. In N2a/APP695 cells, TG treatment attenuated the secretion of Aβ1–40 and Aβ1–42 acting as an PPARγ agonist by inhibiting the translocation of NF-κB p65. Additionally, TG treatment also decreased the expression of amyloidogenic pathway related gene BACE1, PS1 and PS2. Conclusions: TG treatment reduced the production of Aβ both in vivo and in vitro. Activating PPARγ might be a potential therapeutic target of TG in facilitating Aβ clearance and ameliorating cognitive deficiency in APP/PS1 mice.

Aβ oligomers play a central role in the neurodegeneration observed with Alzheimer's disease. Our laboratory has developed covalently stabilized trimers derived from residues 17-36 of Aβ as model systems for studying Aβ oligomers. In the current study, we apply the emerging techniques of fluorescence lifetime imaging microscopy (FLIM) and native mass spectrometry (native MS) to better understand the assembly and interactions of the oligomer model system 2AT-L in aqueous solutions and with cells. 2AT-L and fluorescently labeled 2AT-L analogues assemble in the membrane-like environment of SDS-PAGE, showing diffuse bands of oligomers in equilibrium. Native ion mobility-mass spectrometry (native IM-MS) of 2AT-L allows for the identification of discrete oligomers in solution and shows similar patterns of oligomer formation between 2AT-L and fluorescently labeled analogues. Fluorescence microscopy with SH-SY5Y cells reveals that fluorescently labeled 2AT-L analogues colocalize within lysosomes. FLIM studies with phasor analysis further elucidate the assembly of 2AT-L within cells and establish the occurrence of FRET, indicating the presence of oligomers within cells. Collectively, these multiple complementary techniques help better understand the complex behavior of the 2AT-L model system.

Mitochondrial (mt) DNA can be classified into haplogroups, which represent populations with different geographic origins. Individuals of maternal African backgrounds (L haplogroup) are more prone to develop specific diseases compared those with maternal European-H haplogroups. Using a cybrid model, effects of amyloid-β (Amyβ), sub-lethal ultraviolet (UV) radiation, and 5-Aza-2'-deoxycytidine (5-aza-dC), a methylation inhibitor, were investigated. Amyβ treatment decreased cell metabolism and increased levels of reactive oxygen species in European-H and African-L cybrids, but lower mitochondrial membrane potential (ΔΨM) was found only in African-L cybrids. Sub-lethal UV radiation induced higher expression levels of CFH, EFEMP1, BBC3, and BCL2L13 in European-H cybrids compared to African-L cybrids. With respect to epigenetic status, the African-L cybrids had (a) 4.7-fold higher total global methylation levels (p = 0.005); (b) lower expression patterns for DNMT3B; and (c) elevated levels for HIST1H3F. The European-H and African-L cybrids showed different transcription levels for CFH, EFEMP1, CXCL1, CXCL8, USP25, and VEGF after treatment with 5-aza-dC. In conclusion, compared to European-H haplogroup cybrids, the African-L cybrids have different (i) responses to exogenous stressors (Amyβ and UV radiation), (ii) epigenetic status, and (iii) modulation profiles of methylation-mediated downstream complement, inflammation, and angiogenesis genes, commonly associated with various human diseases.

Abstract Background Hyperhomocysteinemia (HHcy) has been linked to development of Alzheimer’s disease (AD) neuropathologically characterized by the accumulation of amyloid β (Aβ). Microglia (MG) play a crucial role in uptake of Aβ fibrils, and its dysfunction worsens AD. However, the effect of HHcy on MG Aβ phagocytosis remains unstudied. Methods We isolated MG from the cerebrum of HHcy mice with genetic cystathionine-β-synthase deficiency (Cbs −/− ) and performed bulk RNA-seq. We performed meta-analysis over transcriptomes of Cbs −/− mouse MG, human and mouse AD MG, MG Aβ phagocytosis model, human AD methylome, and GWAS AD genes. Results HHcy and hypomethylation conditions were identified in Cbs −/− mice. Through Cbs −/− MG transcriptome analysis, 353 MG DEGs were identified. Phagosome formation and integrin signaling pathways were found suppressed in Cbs −/− MG. By analyzing MG transcriptomes from 4 AD patient and 7 mouse AD datasets, 409 human and 777 mouse AD MG DEGs were identified, of which 37 were found common in both species. Through further combinatory analysis with transcriptome from MG Aβ phagocytosis model, we identified 130 functional-validated Aβ phagocytic AD MG DEGs (20 in human AD, 110 in mouse AD), which reflected a compensatory activation of Aβ phagocytosis. Interestingly, we identified 14 human Aβ phagocytic AD MG DEGs which represented impaired MG Aβ phagocytosis in human AD. Finally, through a cascade of meta-analysis of transcriptome of AD MG, functional phagocytosis, HHcy MG, and human AD brain methylome dataset, we identified 5 HHcy-suppressed phagocytic AD MG DEGs (Flt1, Calponin 3, Igf1, Cacna2d4, and Celsr) which were reported to regulate MG/MΦ migration and Aβ phagocytosis. Conclusions We established molecular signatures for a compensatory response of Aβ phagocytosis activation in human and mouse AD MG and impaired Aβ phagocytosis in human AD MG. Our discoveries suggested that hypomethylation may modulate HHcy-suppressed MG Aβ phagocytosis in AD.

The amyloid cascade hypothesis postulates that extracellular deposits of amyloid β (Aβ) are the primary and initial cause leading to the full development of Alzheimer’s disease (AD) with intracellular neurofibrillary tangles; however, the details of this mechanism have not been fully described until now. Our preliminary data, coming from our day-to-day neuropathology practice, show that the primary location of the hyperphosphorylated tau protein is in the vicinity of the cell membrane of dystrophic neurites. This observation inspired us to formulate a hypothesis that presumes an interaction between low-density lipoprotein receptor-related protein 1 (LRP1) and fibrillar aggregates of, particularly, Aβ42 anchored at the periphery of neuritic plaques, making internalization of the LRP1-Aβ42 complex infeasible and, thus, causing membrane dysfunction, leading to the tauopathy characterized by intracellular accumulation and hyperphosphorylation of the tau protein. Understanding AD as a membrane dysfunction tauopathy may draw attention to new treatment approaches not only targeting Aβ42 production but also, perhaps paradoxically, preventing the formation of LRP1-Aβ42.

Amyloid β peptide (Aβ) aggregation and deposition are considered the main causes of Alzheimer’s disease. In a previous study, we demonstrated that anionic Zn-phthalocyanine (ZnPc) can interact with the Aβ peptide and inhibit the fibril-formation process. However, due to the inability of anionic ZnPc to cross the intact blood–brain barrier, we decided to explore the interaction of cationic methylated Zn-phthalocyanine (cZnPc) with the peptide. Using a ThT fluorescence assay, we observed that cZnPc dose-dependently and time-dependently inhibited Aβ1-42 fibril levels under in vitro fibril-formation conditions. Electron microscopy revealed that it caused Aβ1-42 peptides to form small aggregates. Western blotting and dot immunoblot oligomer experiments demonstrated that cZnPc increased rather than decreased the levels of oligomers from the very early stages of incubation. A binding assay confirmed that cZnPc could bind with the peptide. Docking simulations indicated that the oligomer species of Aβ1-42 had a higher ability to interact with cZnPc. ANS fluorescence assay results indicated that cZnPc did not affect the hydrophobicity of the peptide. However, cZnPc significantly increased intrinsic tyrosine fluorescence of the peptide after 8 h of incubation in fibril-formation conditions. Importantly, cell culture experiments demonstrated that cZnPc did not exhibit any toxicity up to a concentration of 10 µM. Instead, it protected a neuronal cell line from Aβ1-42-induced toxicity. Thus, our results suggest that cZnPc can affect the aggregation process of Aβ1-42, rendering it non-toxic, which could be crucial for the therapy of Alzheimer’s disease.

Alzheimer’s disease (AD) is a neurodegenerative disorder associated with age. A wealth of evidence indicates that the amyloid β (Aβ) aggregates result from dyshomeostasis between Aβ production and clearance, which plays a pivotal role in the pathogenesis of AD. Consequently, therapies targeting Aβ reduction represent a promising strategy for AD intervention. Tetramethylpyrazine nitrone (TBN) is a novel tetramethylpyrazine derivative with potential for the treatment of AD. Previously, we demonstrated that TBN markedly enhanced cognitive functions and decreased the levels of Aβ, APP, BACE 1, and hyperphosphorylated tau in 3×Tg-AD mice. However, the mechanism by which TBN inhibits Aβ deposition is still unclear. In this study, we employed APP/PS1 mice treated with TBN (60 mg/kg, ig, bid) for six months, and N2a/APP695swe cells treated with TBN (300 μM) to explore the mechanism of TBN in Aβ reduction. Our results indicate that TBN significantly alleviated cognitive impairment and reduced Aβ deposition in APP/PS1 mice. Further investigation of the underlying mechanisms revealed that TBN decreased the expression of APP and BACE1, activated the AMPK/mTOR/ULK1 autophagy pathway, inhibited the PI3K/AKT/mTOR/ULK1 autophagy pathway, and decreased the phosphorylation levels of JNK and ERK in APP/PS1 mice. Moreover, TBN was found to significantly reduce the mRNA levels of APP and BACE1, as well as those of SP1, CTCF, TGF-β, and NF-κB, transcription factors involved in regulating gene expression. Additionally, TBN was observed to decrease the level of miR-346 and increase the levels of miR-147 and miR-106a in the N2a/APP695swe cells. These findings indicate that TBN may reduce Aβ levels likely by reducing APP expression by regulating APP gene transcriptional factors and miRNAs, reducing BACE1 expression, and promoting autophagy activities.

With the rapid progress in deciphering the pathogenesis of Alzheimer’s disease (AD), it has been widely accepted that the accumulation of misfolded amyloid β (Aβ) in the brain could cause the neurodegeneration in AD. Although much evidence demonstrates the neurotoxicity of Aβ, the role of Aβ in the nervous system are complex. However, more comprehensive studies are needed to understand the physiological effect of Aβ40 monomers in depth. To explore the physiological mechanism of Aβ, we employed mass spectrometry to investigate the altered proteomic events induced by a lower submicromolar concentration of Aβ. Human neuroblastoma SH-SY5Y cells were exposed to five different concentrations of Aβ1-40 monomers and collected at four time points. The proteomic analysis revealed the time–course behavior of proteins involved in biological processes, such as RNA splicing, nuclear transport and protein localization. Further biological studies indicated that Aβ40 monomers may activate PI3K/AKT signaling to regulate p-Tau, Ezrin and MAP2. These three proteins are associated with dendritic morphogenesis, neuronal polarity, synaptogenesis, axon establishment and axon elongation. Moreover, Aβ40 monomers may regulate their physiological forms by inhibiting the expression of BACE1 and APP via activation of the ERK1/2 pathway. A comprehensive exploration of pathological and physiological mechanisms of Aβ is beneficial for exploring novel treatment.

Surface engineering of nanoparticles has been widely used in biosensing and assays, where sensitivity was mainly limited by plasmonic colour change or electrochemical responses. Here, we report a novel biomimetic sensing strategy involving protein-modified gold nanoparticles (AuNPs), where the modulation strategy was inspired by gastropods in inhibition of coffee-ring effects in their trail-followings. The so-called coffee-ring effect presents the molecular behaviour of AuNPs to a macroscopic ring through aggregation, and thus greatly improves sensitivity. The assay relies upon the different assembly patterns of AuNPs against analytes, resulting in the formation or suppression of coffee-ring effects by the different surface engineering of AuNPs by proteins and peptides. The mechanism of the coffee-ring formation process is examined through experimental characterizations and computational simulations. A practical coffee-ring effect assay is developed for a proof-of-concept target, amyloid β (1–42), which is a typical biomarker of Alzheimer's disease. A novel quasi-titrimetric protocol is constructed for quantitative determination of the target molecule. The assay shows excellent selectivity and sensitivity for the amyloid β monomer, with a low detection limit of 20 pM. Combined with a fluorescent staining technique, the assay is designed as a smart sensor for amyloid β detection and fibrillation evaluation in rat cerebrospinal fluids, which is a potential point-of-care test for Alzheimer's disease. Connections between amyloid fibrillation and different courses of brain ischaemia are also studied, with improved sensitivity, lower sample volumes that are required, convenience for rapid detection, and point-of-care testing. [ABSTRACT FROM AUTHOR]

Despite Alzheimer's Disease (AD) being known from the times of Alois Alzheimer, who lived more than one century ago, many aspects of the disease are still obscure, including the pathogenesis, the clinical spectrum definition, and the therapeutic approach. Well-established biomarkers for AD come from the histopathological hallmarks of the disease, which are Aβ and phosphorylated Tau protein aggregates. Consistently, cerebrospinal fluid (CSF) Amyloid β (Aβ) and phosphorylated Tau level measurements are currently used to detect AD presence. However, two central biases affect these biomarkers. Firstly, incomplete knowledge of the pathogenesis of diseases legitimates the search for novel molecules that, reasonably, could be expressed by neurons and microglia and could be detected in blood simpler and earlier than the classical markers and in a higher amount. Further, studies have been performed to evaluate whether CSF biomarkers can predict AD onset in Mild Cognitive Impairment (MCI) patients. However, the MCI definition has changed over time. Hence, the studies on MCI patients seem to be biased at the beginning due to the imprecise enrollment and heterogeneous composition of the miscellaneous MCI subgroup. Plasma biomarkers and novel candidate molecules, such as microglia biomarkers, have been tentatively investigated and could represent valuable targets for diagnosing and monitoring AD. Also, novel AD markers are urgently needed to identify molecular targets for treatment strategies. This review article summarizes the main CSF and blood AD biomarkers, underpins their advantages and flaws, and mentions novel molecules that can be used as potential biomarkers for AD. [ABSTRACT FROM AUTHOR]

The brain of a rhesus monkey that died at 43 years of age with symptoms of suspected cognitive dysfunction was analyzed. pathological analyses revealed characteristic Alzheimer’s disease-related lesions: the aggregation of amyloid β (Aβ) in the form of senile plaques and phosphorylated tau proteins. We also revealed that Aβ43, which is prone to aggregation and toxicity in humans, is involved in senile plaques in the brain of the rhesus monkey, as well as several other Aβ species. Comparative studies of neuropathology using aged nonhuman primates lack behavioral descriptions compared to human medicine. This case report showed behavioral abnormalities and the detailed pathological changes that may have caused it in a super-aged rhesus monkey [ABSTRACT FROM AUTHOR]

The formation of pathological protein aggregates is associated with many neurodegenerative diseases. The aggregates can form by multilayer adsorption of ligands on a matrix in some cases; for example, the set of membrane protein receptors may act as a matrix. A thermodynamic model was developed to describe the formation of linear aggregates in which ligands are stacked. Cases where complexes of the same type or two different types form the stacks are considered. The model can be used to study pathological aggregation of various proteins and, primarily, amyloid β and its isoforms. The mean, variance, and entropy were calculated for a theoretical distributions of aggregate sizes. A comparison was made with other theoretical models of the formation of amyloid aggregates. [ABSTRACT FROM AUTHOR]

Anti-amyloid therapies (AATs), such as anti-amyloid monoclonal antibodies, are emerging treatments for people with early Alzheimer's disease (AD). AATs target amyloid β plaques in the brain. Amyloid-related imaging abnormalities (ARIA), abnormal signals seen on magnetic resonance imaging (MRI) of the brain in patients with AD, may occur spontaneously but occur more frequently as side effects of AATs. Cerebral amyloid angiopathy (CAA) is a major risk factor for ARIA. Amyloid β plays a key role in the pathogenesis of AD and of CAA. Amyloid β accumulation in the brain parenchyma as plaques is a pathological hallmark of AD, whereas amyloid β accumulation in cerebral vessels leads to CAA. A better understanding of the pathophysiology of ARIA is necessary for early detection of those at highest risk. This could lead to improved risk stratification and the ultimate reduction of symptomatic ARIA. Histopathological confirmation of CAA by brain biopsy or autopsy is the gold standard but is not clinically feasible. MRI is an available in vivo tool for detecting CAA. Cerebrospinal fluid amyloid β level testing and amyloid PET imaging are available but do not offer specificity for CAA vs amyloid plaques in AD. Thus, developing and testing biomarkers as reliable and sensitive screening tools for the presence and severity of CAA is a priority to minimize ARIA complications. [ABSTRACT FROM AUTHOR]

The insulin/IGF-1 signaling (IIS) regulates a wide range of biological processes, including aging and lifespan, and has also been implicated in the pathogenesis of Alzheimer's disease (AD). We and others have reported that reduced signaling by genetic ablation of the molecules involved in IIS (e.g., insulin receptor substrate 2 [IRS-2]) markedly mitigates amyloid plaque formation in the brains of mouse models of AD, although the molecular underpinnings of the amelioration remain unsolved. Here, we revealed, by a transcriptomic analysis of the male murine cerebral cortices, that the expression of genes encoding extracellular matrix (ECM) was significantly upregulated by the loss of IRS-2. Insulin signaling activity negatively regulated the phosphorylation of Smad2 and Smad3 in the brain, and suppressed TGF-β/Smad-dependent expression of a subset of ECM genes in brain-derived cells. The ECM proteins inhibited Aβ fibril formation in vitro, and IRS-2 deficiency suppressed the aggregation process of Aβ in the brains of male APP transgenic mice as revealed by injection of aggregation seeds in vivo. Our results propose a novel mechanism in AD pathophysiology whereby IIS modifies Aβ aggregation and amyloid pathology by altering the expression of ECM genes in the brain. [ABSTRACT FROM AUTHOR]

Organophosphate (OP) is a compound considered the main leading cause of morbidity and mortality from poisoning worldwide. Serum pseudocholinesterase was evaluated as a diagnostic indicator; it cannot be used to monitor therapy or severity of the intoxication. The rationale of the current study was to evaluate sensitivity, specificity, and cut-off values of serum S100B and amyloid β for neurological affection severity. This study was carried out on sixty OP-impaired patients; in addition, 20 normal controls were included. Serum liver and kidney function tests, malondialdehyde, pseudocholinesterase, and the levels of S100B and amyloid β (Aβ) were determined. Data showed that Pearson's analysis indicated that the serum level of S100B was positively correlated with Aβ. On the contrary, the activity of pseudocholinesterase was negatively correlated with both of S100B and Aβ. Serum ALT, AST, creatinine, urea, acetylcholine, and MDA levels were elevated while pseudocholinesterase activity was reduced in moderate and severe OP intoxication versus control. A drastic elevation (p<0.001) in the levels of S100B and Aβ was performed in the patient group suffering from OP intoxication versus the normal group. The diagnostic statistical validation of targeted parameters in distinguishing between moderate OP intoxication and control clarifies that S100B displayed the best AUC (0.997) followed by Aβ (AUC=0.992), while the diagnostic veracity of S100B and Aβ in setting apart severe OP-intoxicated and normal subjects stated the symmetric efficacy of potential markers. It was concluded that the significant changes in the levels of S100B and Aβ were directly proportional to the degree of severity of OP intoxication. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) continues to be a major global health challenge, and the recent approval of Aduhelm and Leqembi has opened new avenues for its treatment. Small‐molecule inhibitors targeting Aβ aggregation hold promise as an alternative to monoclonal antibodies. In this study, we evaluated the ability of berbamine hydrochloride (BBMH), a member of the bisbenzylisoquinoline alkaloids, to reduce Aβ aggregation and cytotoxicity. Thioflavin T kinetics, circular dichroism spectroscopy, and atomic force microscopy results indicated that BBMH effectively inhibited Aβ aggregation. Surface plasmon resonance and molecular docking results further revealed that BBMH could bind to Aβ fibrils, thereby hindering the aggregation process. This physical picture has been confirmed in a quantitative way by chemical kinetics analysis, which showed BBMH tends to bind with the fibril ends and thus prevents the transition from protofibrils to mature fibrils as well as the elongation process. Additionally, our MTT results showed that BBMH was able to reduce the cytotoxicity of Aβ40 on N2a cells. Our results demonstrate, for the first time, the potential of BBMH to inhibit Aβ aggregation and cytotoxicity, offering a promising direction for further research and drug development efforts in the fight against Alzheimer's disease. [ABSTRACT FROM AUTHOR]