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Background: Recent studies suggest that opioid receptor signaling may differentially affect Alzheimer's disease (AD) pathology and the relevant behavioral dysfunctions. However, the precise roles and mechanisms of opioid receptor subtypes in AD pathologies are still unclear with major controversies. Methods: We compared the delta-opioid receptor (DOR)- and mu-opioid receptor (MOR)-mediated effects on AD-associated cognitive deficits, pathologies, neuroinflammations, cell death using transgenic APP/PS1 mouse model and BV2 cell line at behavioral, molecular, and cellular levels. Unpaired t-test and one/two way analysis for variance (ANOVA) were used to analyze statistical significance of the data. Results: We show a distinct role of DOR and its major difference with MOR in AD injury in an APP/PS1 mouse model. DOR activation by UFP-512, but not MOR activation by DAMGO, attenuated cognitive impairment, reduced beta-amyloid (Aβ) production and aggregation, as well as protected the neurons from apoptosis in APP/PS1 mice. DOR and MOR also differentially modulated microglia in APP/PS1 mice and in vitro AD cell model with a DOR-mediated inhibition on the excessive activation of microglia and the release of pro-inflammatory cytokines in AD pathologies. Gene expression profiling further revealed that the alternations in DOR/MOR are closely associated with microglial homeostatic signatures and high mobility group protein B1 (HMGB1) in AD. DOR activation inhibited HMGB1 secretion and its translocation from nuclear to cytoplasm. Our in-vitro studies further confirmed that DOR overexpression mitigated microglial inflammatory response and rescued neurons from AD injury via HMGB1-NF-κB signaling pathway. Conclusions: These novel findings uncover previously unappreciated roles of DOR in neuroprotection against AD injury via modulating microglia-related inflammatory responses. [ABSTRACT FROM AUTHOR]

Background: Accumulation of β-amyloid (Aβ) in the brain is a hallmark of Alzheimer's Disease (AD). Cerebral deposition of Aβ initiates deteriorating pathways which eventually can lead to AD. However, the exact mechanisms are not known. A possible pathway could be that Aβ affects the cerebral vessels, causing inadequate cerebrovascular function. In the present study, we examined if Aβ accumulation is associated with a reduced cerebral blood flow response (CBF) to neuronal activation by visual stimulation (ΔCBFVis.Act.) in cognitively normal subjects from the Metropolit Danish Male Birth Cohort. Methods: 64 subjects participated in the present study. ΔCBFVis.Act. was measured using arterial spin labelling (ASL) combined with blood-oxygen-level-dependent (BOLD) MRI. Neuronal activation was obtained by visual stimulation by a flickering checkerboard presented on a screen in the MRI-scanner. Brain Aβ accumulation and cerebral glucose metabolism were assessed by PET imaging using the radiotracers [11C]Pittsburgh Compound-B (PiB) and [18F]Fluorodeoxyglucose (FDG), respectively. Cortical thickness was measured from structural MRI. Results: ΔCBFVis.Act. correlated negatively (β = -32.1 [95% confidence interval (CI): -60.2; -4.1], r = -0.30, p = 0.025) with PiB standardized uptake value ratio (SUVr) in the brain regions activated by visual stimulation. ΔCBFVis.Act. did not correlate with FDG SUVr (β = 1.9 [CI: -23.8; 27.6], r = 0.02, p = 0.88) or cortical thickness (β = 10.3 [CI: -8.4; 29.0], r = 0.15, p = 0.27) in the activated brain regions. Resting CBF did not correlate with PiB SUVr neither in the regions activated by visual stimulation (β = -17.8 [CI:-71.9; 36.2], r =- 0.09, p = 0.51) nor in the remaining cortex (β = 5.2 [CI:-3.9; 14.2], r = 0.15, p = 0.26). Conclusion: We found a correlation between high PiB SUVr and reduced CBF response to neuronal activation, indicating a link between Aβ accumulation and impaired cerebrovascular function. The impairment was not associated with cortical thinning or hypometabolism, suggesting that Aβ accumulation affecting brain vessel function could be a very early pathology leading to neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Episodic memory (EM) alterations are a hallmark of Alzheimer’s disease (AD). We assessed EM longitudinally in cognitively normal elders at-risk for AD (with subjective memory complaints), as a function of amyloid-β (Aβ) burden, neurodegeneration (N), and progression to prodromal AD. We stratified 264 INSIGHT-preAD study subjects in controls (Aβ-/N−), stable/N− or N + (Aβ +), and progressors/N− or N + (Aβ +) groups (progressors were included only until AD-diagnosis). We used linear mixed-effect models with Aβ and N status, or progression to AD as factors, to analyze behavioral performance in an old/new word-recognition task based on the free and cued selective reminding test (FCSRT). The controls and stable/N− groups showed near-ceiling accuracy and RT improvement across follow-up. The stable/N + group showed accuracy reduction and no RT improvement, i.e., Aβ + /N + cumulative effect. The progressors showed a marked performance decline. EM alterations may constitute early preclinical markers of progression to prodromal AD, while individuals are cognitively normal according to neuropsychological standards. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Its etiology and associated mechanisms are still unclear, which largely hinders the development of AD treatment strategies. Many studies have shown that dysregulation of energy metabolism in the brain of AD is closely related to disease development. Dysregulation of brain energy metabolism in AD brain is associated with reduced glucose uptake and utilization, altered insulin signaling pathways, and mitochondrial dysfunction. In this study, we summarized the relevant pathways and mechanisms regarding the dysregulation of energy metabolism in AD. In addition, we highlight the possible role of mitochondrial dysfunction as a central role in the AD process. A deeper understanding of the relationship between energy metabolism dysregulation and AD may provide new insights for understanding learning memory impairment in AD patients and in improving AD prevention and treatment. [ABSTRACT FROM AUTHOR]

Background: There is a need for faster amyloid PET scans to reduce patients' discomfort, minimize movement artifacts, and increase throughput. The recently introduced uMI Panorama PET/CT system featuring enhanced spatial resolution and sub-200ps TOF offers the potential for shorter scan duration without sacrificing image quality or efficacy to detect Aβ deposition. The study aims to establish a faster acquisition protocol for [18F]florbetapir PET imaging using digital PET/CT scanner uMI Panorama, while ensuring adequate image quality and amyloid-β (Aβ) detectability comparable to the standard 10-minute scan. Methods: Thirty-eight participants (29 Aβ positive and 9 Aβ negative) from a prospective dementia cohort at Peking Union Medical University Hospital underwent routine [18F]florbetapir PET scans using the uMI Panorama PET/CT scanner and a T1-weighted brain MRI scan. List-mode PET data were reconstructed into durations of 10 min, 2 min, 1 min, 45 s, and 30 s (G10min, G2min, G1min, G45s, G30s). Two trained nuclear medicine physicians independently evaluated the image quality using a 5-point scale and provided binary diagnosis. Standardized uptake value ratios (SUVr) of the composite cortex (frontal, lateral parietal, lateral temporal, and cingulate cortices) were calculated to discriminate Aβ status and coefficient of variation assessed objective image quality. Comparisons of image quality and Aβ detectability between various fast scan groups and G10min group were conducted. Results: The subjective image quality evaluation and Aβ detectability results from the two physicians showed both good intra-reader and inter-reader agreements (Cohen's kappa coefficient: 0.759-1.000). The subjective and objective image qualities of the G2min scans were comparable to the G10min scans, whereas adequate image quality was achieved with the G1min and G45s scans (5-point score ≥ 3). Subjective visual diagnosis by two physicians yielded consistent accuracy for G10min, G2min, and G1min groups, but lower specificity for G45s and G30s groups. The objective detection of Aβ status by cortex SUVr across all scan durations maintained perfect discriminatory efficiency and relatively high effect size (Hedge's G: 2.48–2.54). Conclusions: A 1-min ultra-fast scan is feasible for [18F]florbetapir PET imaging using uMI Panorama PET/CT, while maintaining adequate image quality and Aβ diagnostic efficiency. Clinical trial registration: NCT05023564. Registered September 2022 https://clinicaltrials.gov/search?term=NCT05023564. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) biomarkers of synaptic dysfunction, neuroinflammation, and glial response, complementing Alzheimer's disease (AD) core biomarkers, have improved the pathophysiological characterization of the disease. Here, we tested the hypothesis that the co-expression of multiple CSF biomarkers will help the identification of AD-like phenotypes when biomarker positivity thresholds are not met yet. Methods: Two hundred and seventy cognitively unimpaired adults with family history (FH) of sporadic AD (mean age = 60.6 ± 4.85 years, 64.8% women) underwent lumbar puncture, magnetic resonance imaging (n = 266) and positron emission tomography imaging (n = 239) protocols, and clinical evaluations. CSF Aβ42, Aβ40, p-tau181, p-tau217, p-tau231, NfL, neurogranin, sTREM2, YKL40, GFAP, S100, α-Synuclein, SYT1, and SNAP25 were measured. Participants were clustered based on CSF biomarker co-expression with an agglomerative algorithm. The predictive value of the classification against brain and cognitive outcomes was evaluated. Results: Three clusters (C) were identified. Higher Aβ burden and CSF p-tau was the hallmark of C1. The other two clusters showed lower Aβ burden but higher expression of glial (C2) or synaptic markers (C3). Participants in C1 showed an AD-like clinical phenotype, comprising participants with the overall highest percentage of two parent FH and APOE-ε4 carriers, in addition to comprising more females compared to C2. C3 displayed better vascular health compared to C1. C2 were older and comprised a lower percentage of females compared to C3. C1 showed an AD-like gray matter reduction in medial temporal (notably hippocampus) and frontal regions that were not observed in Aβ42/40 + compared with Aβ42/40 −. Furthermore, Aβ42/40 − participants in C1 showed GM reduction in inferior temporal areas compared with Aβ42/40 + participants overall. C1 membership also predicted cognitive decline in executive function, but not memory, beyond Aβ + status, overall suggesting a better prognosis in Aβ42/40 + participants without C1 membership. Additionally, C1 displayed a higher rate of conversion to Aβ + (25%) over time. Conclusions: Our results suggest that examining multiple CSF biomarkers reflecting diverse pathological pathways may complement and/or outperform AD core biomarkers and thresholding approaches to identify individuals showing a clinical and cognitive AD-like phenotype, including higher conversion to Aβ + , GM reductions and cognitive decline. The clinical utility of this approach warrants further investigation and replication in other cohorts. [ABSTRACT FROM AUTHOR]

Recently, the glymphatic system has been proposed as a mechanism for waste clearance from the brain parenchyma. Glymphatic dysfunction has previously been shown to be associated with several neurological diseases, including Alzheimer's disease, traumatic brain injury, and stroke. As such, it may serve as an important target for therapeutic interventions. In the present study, very low‐intensity ultrasound (VLIUS) (center frequency, 1 MHz; pulse repetition frequency, 1 kHz; duty factor, 1%; spatial peak temporal average intensity [Ispta] = 3.68 mW cm2; and duration, 5 min) is found to significantly enhance the influx of cerebrospinal fluid tracers into the paravascular spaces of the brain, and further facilitate interstitial substance clearance from the brain parenchyma, including exogenous β‐amyloid. Notably, no evidence of brain damage is observed following VLIUS stimulation. VLIUS may enhance glymphatic influx via the transient receptor potential vanilloid‐4‐aquaporin‐4 pathway in astrocytes. This mechanism may provide insights into VLIUS‐regulated glymphatic function that modifies the natural course of central nervous system disorders related to waste clearance dysfunction. [ABSTRACT FROM AUTHOR]

Background: The CD2-associated protein (CD2AP) was initially identified in peripheral immune cells and regulates cytoskeleton and protein trafficking. Single nucleotide polymorphisms (SNPs) in the CD2AP gene have been associated with Alzheimer's disease (AD). However, the functional role of CD2AP, especially its role in microglia during AD onset, remains elusive. Methods: CD2AP protein levels in cultured primary cells and in 5xFAD mice was studied. Microglial CD2AP-deficient mice were crossed with 5xFAD mice and the offspring were subjected to neuropathological assessment, behavioral tests, electrophysiology, RNA-seq, Golgi staining, and biochemistry analysis. Primary microglia were also isolated for assessing their uptake and morphology changes. Results: We find that CD2AP is abundantly expressed in microglia and its levels are elevated in the brain of AD patients and the 5xFAD model mice at pathological stages. We demonstrate that CD2AP haploinsufficiency in microglia significantly attenuates cognitive and synaptic deficits, weakens the response of microglia to Aβ and the formation of disease-associated microglia (DAM), and alleviates synapse loss in 5xFAD mice. We show that CD2AP-deficient microglia exhibit compromised uptake ability. In addition, we find that CD2AP expression is positively correlated with the expression of the complement C1q that is important for synapse phagocytosis and the formation of DAM in response to Aβ deposition. Moreover, we reveal that CD2AP interacts with colony stimulating factor 1 receptor (CSF1R) and regulates CSF1R cell surface levels, which may further affect C1q expression. Conclusions: Our results demonstrate that CD2AP regulates microgliosis and identify a protective function of microglial CD2AP deficiency against Aβ deposition, suggesting the importance of detailed investigation of AD-associated genes in different brain cells for thoroughly understanding their exact contribution to AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder of complex pathogenesis and multiple interacting signaling pathways where amyloidal-β protein (Aβ) clearance plays a crucial role in cognitive decline. Herein, the current study investigated the possible modulatory effects of memantine/ rosuvastatin therapy on TGF-β1/p-Smad/p21 signaling pathway and their correlation to the blood brain barrier transporters involved in Aβ-clearance and microRNAs as a novel molecular mechanism in AD treatment. AD was induced by a single intracerebroventricular streptozotocin injection (ICV-STZ, 3 mg/kg) in rats and drug therapy was continued for 28 days after AD induction. Efficacy was monitored by applying a battery of behavioral assessments, as well as biochemical, histopathological, molecular and gene expression techniques. The upregulated TGF-β1-signaling in the untreated rats was found to be highly correlated to transporters and microRNAs governing Aβ-efflux; ABCA1/miRNA-26 and LRP1/miRNA-205 expressions, rather than RAGE/miRNA-185 controlling Aβ-influx; an effect that was opposed by the tested drugs and was found to be correlated with the abolished TGF-β1-signaling as well. Combined memantine/rosuvastatin therapy ameliorated the STZ evoked decreases in escape latency and number of crossovers in the Morris water maze test, % spontaneous alternation in the Y-maze test, and discrimination and recognition indices in the object recognition test. The evoked behavioral responses were directly related to the β-amyloid accumulation and the alteration in its clearance. Additionally, drug treatment increased brain glutathione and decreased malondialdehyde levels. These findings were histopathologically confirmed by a marked reduction of gliosis and restoration of neuronal integrity in the CA1 region of the hippocampus of the AD rats. These findings implicated that the memantine/rosuvastatin combination could offer a new therapeutic potential for AD management by abrogating the TGF-β1/p-Smad2/p21 pathway and regulating Aβ-clearance. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease mainly caused by β-amyloid (Aβ) accumulation in the brain. Among the several factors that may concur to AD development, elevated cholesterol levels and brain cholesterol dyshomeostasis have been recognized to play a relevant role. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein primarily known to regulate plasma low-density lipoproteins (LDLs) rich in cholesterol and to be one of the main causes of familial hypercholesterolemia. In addition to that, PCSK9 is also recognized to carry out diverse important activities in the brain, including control of neuronal differentiation, apoptosis, and, importantly, LDL receptors functionality. Moreover, PCSK9 appeared to be directly involved in some of the principal processes responsible for AD development, such as inflammation, oxidative stress, and Aβ deposition. On these bases, PCSK9 management might represent a promising approach for AD treatment. The purpose of this review is to elucidate the role of PCSK9, whether or not cholesterol-related, in AD pathogenesis and to give an updated overview of the most innovative therapeutic strategies developed so far to counteract the pleiotropic activities of both humoral and brain PCSK9, focusing in particular on their potentiality for AD management. [ABSTRACT FROM AUTHOR]

Background: Rapid eye movement sleep behavior disorder (RBD) is linked to the diffuse‐malignant subtype and higher cognitive burden in Lewy body disease (LBD). Objective: This study explores brain β‐amyloid deposition and its association with cognitive decline across the RBD–LBD continuum. Methods: Patients with isolated RBD (iRBD), Parkinson's disease with probable RBD (PDRBD), and dementia with Lewy bodies with probable RBD (DLBRBD) underwent 18F‐florbetaben positron emission tomography, 3T magnetic resonance imaging scans, and comprehensive neuropsychological assessments. Subjects were categorized as cognitively normal (NC), mild cognitive impairment (MCI), or dementia. Global and regional standardized uptake value ratios (SUVR) were estimated in predefined cognitive volumes of interest (VOI) derived from voxel‐wise comparison analysis among the cognitive groups, namely the prefrontal, parietal, precentral cortices, lingual gyrus, and supplementary motor area. Generalized linear models assessed the relationship between 18F‐florbetaben SUVRs and neuropsychological testing, adjusting for age and sex. Subgroup analysis focused on the polysomnography‐confirmed iRBD‐continuum subset (n = 41) encompassing phenoconverters and nonconverters in our prospective iRBD cohort. Results: Eighty‐six subjects were classified as follows: 14 NC, 54 MCI, and 18 dementia. The proportion of positive β‐amyloid scans increased with advanced cognitive stages (P = 0.038). β‐Amyloid signals in cognitive VOIs were elevated in subgroups showing impairment in Trail‐Making Test B (TMT‐B). A linear association between TMT‐B z score and global cortical β‐amyloid levels was observed in the iRBD‐continuum subset (P = 0.013). Conclusion: Cortical β‐amyloid accumulates with declines in executive function within the RBD–LBD continuum. TMT‐B performance may be a useful marker associating with β‐amyloid load, particularly in the iRBD population. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders have long existed with few to no methods to cure them. One such disorder is Alzheimer's, which implies the accumulation of β-amyloid plaques in the nervous system. Recently, nanotechnology has been under use for the treatment of several disorders. Especially the use of phytochemicals in their nanoformulations is preferred. Quercetin, a phytochemical, when conjugated with polyvinylpyrrolidone, is expected to show a neuroprotective effect due to its anti-oxidative properties. In this study, the Aβ42 mutant of Drosophila melanogaster is used to analyse the impact and quantify the appropriate concentration at which the most enhanced effect of quercetin and Q-PVP is obtained. The improvement in the motor activity of the mutants was studied by crawling and climbing experiments. The mutants have a characteristic small, narrow and dark pigmented eye with abnormal structure in specific regions. The eye phenotype changes are considered as a parameter to justify the amyloid disintegration. Thioflavin T staining was also used to detect amyloid clearance or disintegration in the treated mutants' eyes and brains. The current study suggests that quercetin can degrade the amyloid plaque in the Aβ42 mutant of D. melanogaster. [ABSTRACT FROM AUTHOR]

Background: The levels of β-amyloid precursor protein (β-APP), tau protein, and phosphorylation of tau (p-tau) protein were examined by quantitative immunohistochemistry in the spinal cord sections of mice suffering from experimental autoimmune encephalomyelitis (EAE) in the successive phases of the disease: onset, peak, and chronic. Methods: EAE was induced in C57BL/6 mice by immunization with MOG35–55 peptide. The degree of pathological changes was assessed in cross-sections of the entire spinal cord. Results: β-APP expression was observed in the white matter and colocalized with some Iba-1-positive macrophages/microglia. It increased in the peak phase of EAE and remained at the same level in the chronic phase. During the onset and peak phases of EAE, expression of tau protein was observed in nerve fibers and nerve cell perikaryons, with a predominance of nerve fibers, whereas in the chronic phase, tau was labeled mainly in the perikaryons of nerve cells, with its content significantly decreased. P-tau immunostaining was seen only in nerve fibers. Conclusions: The expression of p-tau increased with the progression of EAE, reaching the maximum in the chronic phase. The correlation between these proteins and neurodegeneration/neuroinflammation highlights their potential roles in the progression of neurodegenerative mechanisms in MS. [ABSTRACT FROM AUTHOR]

Relevance. Alzheimer’s disease (AD) is the most cause of disability and dementia, which is the 7th leading cause of death worldwide. Diagnosis of AD includes detection of amyloid plaques and hyperphosphorylated tau protein (pTau) in the brain. However, in recent years the amyloid hypothesis of AD development has been criticized and revised, and a growing pool of data emerges indicating more complex pathogenetic mechanisms leading to neurodegeneration in AD. The aim of our work was to evaluate the presence and distribution of amyloid plaques and pTau fragments in different regions of the cerebral cortex in patients 60 years old with diagnosed dementia and without cognitive impairment, as well as in people 60 years old. Materials and Methods. The amount of β-amyloid and pTau fragments in three groups of patients was measured on IHC stained histological sections in the regions of parahippocampal, temporal, and occipital cortex. Results and Discussion. Amyloid plaques were detected in all patients over 60 years of age (with and without dementia), while in younger individuals 60 years of age they were found in 66% of cases. The largest amyloid-β burden was observed in the occipital cortex. pTau was detected in all cortical areas in the three groups of patients. Also, the amount of pTau was higher in the occipital cortex in patients over 60 years of age both with and without dementia than in the group of people under 60 years of age. Conclusion. Thus, accumulation of pTau occurs earlier than β-amyloid. The amount of pTau was higher in patients over 60 years of age with clinically manifested dementia, while in some regions the amount of amyloid conglomerates is higher in cognitively intact patients. The findings point to much more complex mechanisms of the neurodegenerative diseases development with the formation of amyloid plaques being a consequence rather than cause of the disease.

BackgroundKinetic modeling of 18F-florbetaben provides important quantification of brain amyloid deposition in research and clinical settings but its use is limited by the requirement of arterial blood data for quantitative PET. The total-body EXPLORER PET scanner supports the dynamic acquisition of a full human body simultaneously and permits noninvasive image-derived input functions (IDIFs) as an alternative to arterial blood sampling. This study quantified brain amyloid burden with kinetic modeling, leveraging dynamic 18F-florbetaben PET in aorta IDIFs and the brain in an elderly cohort.Methods18F-florbetaben dynamic PET imaging was performed on the EXPLORER system with tracer injection (300 MBq) in 3 individuals with Alzheimer's disease (AD), 3 with mild cognitive impairment, and 9 healthy controls. Image-derived input functions were extracted from the descending aorta with manual regions of interest based on the first 30 s after injection. Dynamic time-activity curves (TACs) for 110 min were fitted to the two-tissue compartment model (2TCM) using population-based metabolite corrected IDIFs to calculate total and specific distribution volumes (VT, Vs) in key brain regions with early amyloid accumulation. Non-displaceable binding potential ([Formula: see text] was also calculated from the multi-reference tissue model (MRTM).ResultsAmyloid-positive (AD) patients showed the highest VT and VS in anterior cingulate, posterior cingulate, and precuneus, consistent with [Formula: see text] analysis. [Formula: see text]and VT from kinetic models were correlated (r² = 0.46, P

Chi-Chen Huang,1 Sheng-Feng Tsai,2,3 Shu-Cheng Liu,4 Mei-Chen Yeh,5 Hao-Chang Hung,5 Chu-Wan Lee,6 Ching-Li Cheng,6 Pei-Ling Hsu,7– 9 Yu-Min Kuo2,3 1Division of Neurosurgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 70403, Taiwan; 2Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan; 3Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan; 4Department of Anesthesiology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 70403, Taiwan; 5Division of Endocrinology and Metabolism, Department of Internal Medicine, Chi Mei Medical Center, Tainan, 71004, Taiwan; 6Department of Nursing, National Tainan Junior College of Nursing, Tainan, 700007, Taiwan; 7Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; 8Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, 80708, Taiwan; 9Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, 80708, TaiwanCorrespondence: Pei-Ling Hsu, Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung, Taiwan, 80708, Tel +886-7-3121101 ext. 2144#16, Fax +886-7-3119849, Email plhsu@kmu.edu.tw Yu-Min Kuo, Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, 1 Ta Hsueh Road, Tainan, 70101, Taiwan, Tel +886-6-2353535 ext. 5294, Fax +886-6-2093007, Email kuoym@mail.ncku.edu.twIntroduction: Insulin, the key hormone for glucose regulation, has garnered attention for its role as an immune modulator. Impaired insulin signaling in the central nervous system is linked to neuroinflammation and neurodegenerative diseases. Microglia, the resident macrophage-like immune cells in the brain, are key regulators of neuroinflammation. However, the mechanisms by which insulin influences microglial immune responses remain relatively unknown.Methods: This study aimed to assess the effects of post-treatment with insulin [30 minutes after lipopolysaccharide (LPS) exposure] on LPS-induced inflammatory responses in BV2 microglial cells.Results: Post-treatment with insulin potentiated LPS-induced production of nitric oxide and pro-inflammatory cytokines, such as TNF and IL-6, through activation of the Akt/NF-κB pathway. Insulin also enhanced the ability of BV2 cells to phagocytose bacteria particles and β-amyloid fibrils. Conversely, insulin inhibited activation of NADPH oxidase and reduced intracellular levels of reactive oxygen species in LPS-treated BV2 cells.Conclusion: Insulin enhances microglial immune competence when challenged by endotoxins but mitigates oxidative stress in these cells. Keywords: β-amyloid, p47phox, phagocytosis, superoxide dismutase

Introduction: Osteoarthritis (OA) is a prevalent chronic joint disorder. It is characterized by an immune response that maintains a low level of inflammation throughout its progression. During OA, cartilage degradation leads to the release of damage-associated molecular patterns (DAMPs), which intensify the inflammatory response. β-Amyloid is a well-recognized DAMP in OA, can interact with APOE isoforms. Methods: This study identified DAMPs-related genes in OA using bioinformatics techniques. Additionally, we examined the expression levels of β-amyloid and apolipoprotein E (ApoE) isoforms by enzyme-linked immunosorbent assay. Results: We identified 10 key genes by machine learning techniques. Immune infiltration analysis revealed upregulation of various immune cell types in OA cartilage, underscoring the critical role of inflammation in OA pathogenesis. In the validation study, elevated serum levels of β-amyloid in knee osteoarthritis (KOA) patients were confirmed, showing positive correlations with ApoE2 and ApoE4. Notably, ApoE3 was identified as an independent protective factor against KOA. Conclusion: In this bioinformatics analysis, we identified the DAMPs-related genes of KOA and explored their potential functions and regulatory networks. The high expression of β-amyloid in KOA was confirmed by experiments, and the correlation between β-amyloid and ApoE2, ApoE4 in KOA was revealed for the first time, this provides a new way to explore the pathogenesis of KOA and to study the therapeutic targets of KOA.

Abstract Alzheimer’s disease (AD) is the most common neurodegenerative disorder, characterized pathologically by extracellular deposition of β-amyloid (Aβ) into senile plaques and intracellular accumulation of hyperphosphorylated tau (pTau) as neurofibrillary tangles. Clinically, AD patients show memory deterioration with varying cognitive dysfunctions. The exact molecular mechanisms underlying AD are still not fully understood, and there are no efficient drugs to stop or reverse the disease progression. In this review, we first provide an update on how the risk factors, including APOE variants, infections and inflammation, contribute to AD; how Aβ and tau become abnormally accumulated and how this accumulation plays a role in AD neurodegeneration. Then we summarize the commonly used experimental models, diagnostic and prediction strategies, and advances in periphery biomarkers from high-risk populations for AD. Finally, we introduce current status of development of disease-modifying drugs, including the newly officially approved Aβ vaccines, as well as novel and promising strategies to target the abnormal pTau. Together, this paper was aimed to update AD research progress from fundamental mechanisms to the clinical diagnosis and therapies.

Alzheimer's disease is a progressive neurodegenerative disorder characterized by mitochondria dysfunction, accumulation of beta-amyloid plaques, and hyperphosphorylated tau tangles in the brain leading to memory loss and cognitive deficits. There is currently no cure for this condition, but the potential of stem cells for the therapy of neurodegenerative pathologies is actively being researched. This review discusses preclinical and clinical studies that have used mouse models and human patients to investigate the use of novel types of stem cell treatment approaches. The findings provide valuable insights into the applications of stem cell-based therapies and include the use of neural, glial, mesenchymal, embryonic, and induced pluripotent stem cells. We cover current studies on stem cell replacement therapy where cells can functionally integrate into neural networks, replace damaged neurons, and strengthen impaired synaptic circuits in the brain. We address the paracrine action of stem cells acting via secreted factors to induce neuroregeneration and modify inflammatory responses. We focus on the neuroprotective functions of exosomes as well as their neurogenic and synaptogenic effects. We look into the shuttling of mitochondria through tunneling nanotubes that enables the transfer of healthy mitochondria by restoring the normal functioning of damaged cells, improving their metabolism, and reducing the level of apoptosis. [ABSTRACT FROM AUTHOR]

Aims: Many factors affect the neuroinflammatory response in patients with Alzheimer disease (AD). Galectin‐3 (Gal‐3) is closely related to microglial activation in the nervous system and can promote the aggregation of cancer cells in tumors. This study aimed to investigate the mechanism by which farnesylthiosalicylic acid (FTS) affects neuroinflammation in Aβ1–42 mice through Gal‐3. Methods: We used the Morris water maze, reverse transcription–polymerase chain reaction (RT–PCR), Western blotting, enzyme‐linked immunosorbent assay (ELISA), and immunofluorescence to conduct our study. Results: FTS reduced the levels of proinflammatory factors and microglial activation in Aβ1–42 mice. FTS inhibited total and membrane expression levels of Gal‐3 in Aβ1–42 mice, and the anti‐inflammatory effect of FTS was reversed by Gal‐3–adeno‐associated viral (AAV). FTS reduced the expression levels of toll‐like receptors (TLRs), effects that were reversed by Gal‐3‐AAV. Moreover, FTS ameliorated Aβ oligomerization and accumulation in Aβ1–42 mice, effects that were also reversed by Gal‐3‐AAV. FTS, through the inhibition of the Gal‐3–c‐Jun N‐terminal kinase (JNK) pathway, reduced PS1 expression; in addition, inhibition of Gal‐3 increased the Aβ‐degrading enzymes in Aβ1–42 mice. FTS‐induced improvements in cognition in Aβ1–42 mice were reversed by Gal‐3‐AAV. Conclusion: FTS may through inhibiting Gal‐3 reduce the expression of TLR4 and CD14 and alleviate Aβ pathology, downregulating Aβ‐stimulated TLR2, TLR4, and CD14 expression, and thus alleviate neuroinflammation in Aβ1–42 mice. [ABSTRACT FROM AUTHOR]

Chloroalkylene amide derivatives were obtained by acylation of known Cholinesterase inhibitors, ipidacrine and tacrine. The acylated derivatives were used in the alkylation of substituted 2-thiouracils (R = Me, CF2H, CF3, (CF2)2H)) for the synthesis of new hybrid compounds. Study of the esterase profile revealed a pronounced activity and selectivity of the obtained conjugates against butyrylcholinesterase (IC50 up to 2.03 µmol L−1), moderate displacement of propidium from the acetylcholinesterase peripheral anionic site, and moderate inhibition of the β-amyloid self-aggregation. It was found that conjugation of thiouracils with tacrine leads to a decrease in the hepatotoxicity of the hybrid compounds compared to that of tacrine, while in the case of ipidacrine derivatives, no hepatotoxicity was observed. [ABSTRACT FROM AUTHOR]

Individual differences in responsiveness to environmental factors, including stress reactivity and anxiety levels, which differ between high (HR) and low (LR) responders to novelty, might be risk factors for development of memory and anxiety disorders in sporadic Alzheimer's disease (sAD). In the present study, we investigated whether behavioral characteristics of the HR and LR rats, influence the progression of sAD (neuroinflammation, β-amyloid peptide, behavioral activity related to memory (Morris water maze) and anxiety (elevated plus maze, white and illuminated open field test) in streptozotocin (STZ)-induced neuroinflammation as a model of early pathophysiological alterations in sAD. Early (45 days) in disease progression, there was a more severe impairment of reference memory and higher levels of anxiety in HRs compared with LRs. Behavioral depression in HRs was associated with higher expression of β-amyloid deposits, particularly in the NAcS, and activation of microglia (CD68+ cells) in the hypothalamus, as opposed to less inflammation in the hippocampus, particularly in CA1, compared with LRs in late (90 days) sAD progression. Our findings suggest that rats with higher behavioral activity and increased responsivity to stressors show more rapid progression of disease and anxiety disorders compared with low responders to novelty in the STZ-induced sAD model. [ABSTRACT FROM AUTHOR]

Recent advances in clinical passive immunotherapy have provided compelling evidence that eliminating amyloid-β (Aβ) slows cognitive decline in Alzheimer's disease (AD). However, the modest benefits and side effects observed in clinical trials indicate that current immunotherapy therapy is not a panacea, highlighting the need for a deeper understanding of AD mechanisms and the significance of early intervention through optimized immunotherapy or immunoprevention. This review focuses on the centrality of Aβ pathology in AD and summarizes recent clinical progress in passive and active immunotherapies targeting Aβ, discussing their lessons and failures to inform future anti-Aβ biotherapeutics design. Various delivery strategies to optimize Aβ-targeting immunotherapies are outlined, highlighting their benefits and drawbacks in overcoming challenges such as poor stability and limited tissue accessibility of anti-Aβ biotherapeutics. Additionally, the perspectives and challenges of immunotherapy and immunoprevention targeting Aβ are concluded in the end, aiming to guide the development of next-generation anti-Aβ immunotherapeutic agents towards improved efficacy and safety. We review the recent advances in amyloid-β-targeting passive and active immunotherapy, and summarize versatile delivery strategies to guide the development of next-generation antibodies and vaccines with improved efficacy and safety. [Display omitted] [ABSTRACT FROM AUTHOR]

In the search for Alzheimer's disease (AD) therapies, most animal models focus on familial AD, which accounts for a small fraction of cases. The majority of AD cases arise from stress factors, such as oxidative stress, leading to neurological changes (sporadic AD). Early in AD progression, dysfunction in γ-secretase causes the formation of insoluble Aβ1-42 peptides, which aggregate into senile plaques, triggering neurodegeneration, cognitive decline, and circadian rhythm disturbances. To better model sporadic AD, we used a new AD rat model induced by intracerebroventricular administration of Aβ1-42 oligomers (icvAβ1-42) combined with melatonin deficiency via pinealectomy (pin). We validated this model by assessing spatial memory using the radial arm maze test and measuring Aβ1-42 and γ-secretase levels in the frontal cortex and hippocampus with ELISA. The icvAβ1-42 + pin model experienced impaired spatial memory and increased Aβ1-42 and γ-secretase levels in the frontal cortex and hippocampus, effects not seen with either icvAβ1-42 or the pin alone. Chronic melatonin treatment reversed memory deficits and reduced Aβ1-42 and γ-secretase levels in both structures. Our findings suggest that our icvAβ1-42 + pin model is extremely valuable for future AD research. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is associated with the accumulation of β-amyloids (Aβs) and the formation of Aβ plaques in the brain. Various structural forms and isoforms of Aβs that have variable propensities for oligomerization and toxicity and may differentially affect the development of AD have been identified. In addition, there is evidence that β-amyloids are engaged in complex interactions with the innate and adaptive immune systems, both of which may also play a role in the regulation of AD onset and progression. In this review, we discuss what is currently known about the intricate interplay between β-amyloids and the immune response to Aβs with a more in-depth focus on the possible roles of B cells in the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

The aggregation of β‐amyloid peptide (Aβ) is associated with neurodegenerative diseases such as Alzheimer's disease (AD). Several therapies aimed at reducing the aggregation of this peptide have emerged as potential strategies for the treatment of AD. This paper describes the design and preparation of new hybrid molecules based on steroids, selenosugars, and [60]fullerene as potential inhibitors of Aβ oligomerization. These moieties were selected based on their antioxidant properties and possible areas of interaction with the Aβ. Cyclopropanations between C60 and malonates bearing different steroid and selenosugar moieties using the Bingel–Hirsch protocol have enabled the synthesis of functionalized molecular hybrids. The obtained derivatives were characterized by physical and spectroscopic techniques. Theoretical calculations for all the selenium compounds were performed using the density functional theory DFT/B3LYP‐D3(BJ)/6‐311G(2d,p) predicting the most stable conformations of the synthesized derivatives. Relevant geometrical parameters were investigated to relate the stereochemical behavior and the spectroscopic data obtained. The affinity of the compounds for Aβ‐peptide was estimated by molecular docking simulation, which predicted an increase in affinity and interactions for Aβ for the hybrids containing the C60 core. In addition, parameters such as lipophilicity, polar surface area, and dipole moment were calculated to predict their potential interaction with membrane cells. [ABSTRACT FROM AUTHOR]

Sleep is considered closely related to cognitive function, and cognitive impairment is the main clinical manifestation of Alzheimer's disease (AD). Sleep disturbance in AD patients is more severe than that in healthy elderly individuals. Additionally, sleep deprivation reportedly increases the activity of the hypothalamic orexin system and the risk of AD. To investigate whether intervention with the orexin system can improve sleep disturbance in AD and its impact on AD pathology. In this study, six-month-old amyloid precursor protein/presenilin 1 mice were subjected to six weeks of chronic sleep deprivation and injected intraperitoneally with almorexant, a dual orexin receptor antagonist (DORA), to investigate the effects and mechanisms of sleep deprivation and almorexant intervention on learning and memory in mice with AD. We found that sleep deprivation aggravated learning and memory impairment and increased brain β-amyloid (Aβ) deposition in mice with AD. The application of almorexant can increase the total sleep time of sleep-deprived mice and reduce cognitive impairment and Aβ deposition, which is related to the improvement in Aquaporin-4 polarity. Thus, DORA may be an effective strategy for delaying the progression of AD patients by improving the sleep disturbances. • Almorexant intervention can alleviate chronic sleep deprivation-induced AD learning and memory impairment and Aβ deposition. • The mechanism may be related to mitigating the damage to AQP4 polarity caused by sleep deprivation. • Orexin dual receptor antagonists can be an effective strategy for improving sleep in AD, and slowing pathological progression. [ABSTRACT FROM AUTHOR]

Highlights: Progressive Supranuclear Palsy (PSP) presents with various clinical phenotypes, making accurate diagnosis difficult. No biomarker systems, such as the AT(N) system for Alzheimer's Disease (AD), have been established yet. In PSP, core AD cerebrospinal fluid biomarkers show a unique pattern, where Aβ42, Aβ40, p-tau, and t-tau levels are decreased while NfL levels are remarkably increased. Progressive Supranuclear Palsy (PSP) is the most common four-repeat tauopathy. PSP cases are typically characterized by vertical gaze palsy and postural instability; however, various phenotypes have been reported, making antemortem diagnosis based on clinical symptoms challenging. The development of biomarkers reflecting brain pathology and the ability to diagnose patients based on these biomarkers are essential for developing future intervention strategies, including disease-modifying therapies. However, despite many dedicated efforts, no highly specific fluid biomarker for PSP has yet been established. Conversely, several cerebrospinal fluid (CSF) biomarkers of Alzheimer's Disease (AD) have been established, and an AT(N) classification system has been proposed. Typically, among patients with AD, CSF amyloid β42 (Aβ42), but not Aβ40, is decreased, resulting in a reduction in the Aβ42/Aβ40 ratio, while tau phosphorylated at threonine 181 (p-tau181) and total tau (t-tau) are increased. Interestingly, the core CSF AD biomarkers show unique patterns in patients with PSP. Furthermore, reports have indicated that the CSF levels of both Aβ42 and Aβ40 are decreased independently of Aβ accumulation in PSP. Therefore, the Aβ42/Aβ40 ratio could potentially be used to differentiate PSP from AD. Additionally, studies have reported that CSF p-tau and t-tau are reduced in PSP, and that the neurofilament light chain is remarkably increased compared to healthy controls and patients with AD, even though PSP is a neurodegenerative disease associated with tau accumulation. These PSP-specific changes in AD-related core biomarkers may reflect the pathology of PSP and contribute to its diagnosis. As such, elucidating the mechanisms underlying the observed decreases in Aβ and tau levels could facilitate a better understanding of the pathogenesis of PSP. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized pathologically by extracellular deposition of β-amyloid (Aβ) into senile plaques and intracellular accumulation of hyperphosphorylated tau (pTau) as neurofibrillary tangles. Clinically, AD patients show memory deterioration with varying cognitive dysfunctions. The exact molecular mechanisms underlying AD are still not fully understood, and there are no efficient drugs to stop or reverse the disease progression. In this review, we first provide an update on how the risk factors, including APOE variants, infections and inflammation, contribute to AD; how Aβ and tau become abnormally accumulated and how this accumulation plays a role in AD neurodegeneration. Then we summarize the commonly used experimental models, diagnostic and prediction strategies, and advances in periphery biomarkers from high-risk populations for AD. Finally, we introduce current status of development of disease-modifying drugs, including the newly officially approved Aβ vaccines, as well as novel and promising strategies to target the abnormal pTau. Together, this paper was aimed to update AD research progress from fundamental mechanisms to the clinical diagnosis and therapies. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder, in which there is a progressive deterioration of intellectual and social functions, memory loss, personality changes and inability for self-care, and has become the fourth leading cause of death in developed countries. Pathogenesis of AD, there is a progressive deposition of β-amyloid (Aβ)- peptide in the hippocampal and cerebral cortical regions. This deposition is associated with the presence of neurofibrillary tangles (NFTs) and senile plaques. The senile plaques deposited between the neurons consist mainly protein β amyloid. Neurofibrillary tangles deposited inside the neurons fabricated from Tau protein. Diagnosing Alzheimer's requires careful medical evaluation thorough medical history, mental status testing, physical and neurological examination tests (such as blood tests and brain imaging), two classes of medications approved to treat AD. Cholinesterase inhibitors: Donepezil, Rivastigmine, Galantamine, NMDA receptor antagonists: Memantine. The major goal in designing nanoparticles as a delivery system are to control particle size, surface property and release of pharmacologically active agents in order to achieve the site-specific action of the drug at the therapeutic optimum rate and dose regimen of the agent to the CNS, but also the ability of the agent to access the relevant target site within the CNS. Many strategies have been developed to deliver the drug into brain by crossing the BBB: chemical delivery systems, magnetic drug targeting or drug carrier systems such as antibodies, liposomes or nanoparticles. Among those, nanoparticles have got a great concentration as the potential targeted drug delivery systems in the brain recently. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is common among military veterans and has been associated with an increased risk of dementia. It is unclear if this is due to increased risk for Alzheimer's disease (AD) or other mechanisms. This case control study sought evidence for AD, as defined by the 2018 National Institute on Aging - Alzheimer's Association (NIA-AA) research framework, by measuring tau, β-amyloid, and glucose metabolism using positron emission tomography (PET) in veterans with service-related TBI. Seventy male Vietnam war veterans-40 with TBI (age 68.0 ± 2.5 years) and 30 controls (age 70.1 ± 5.3 years)-with no prior diagnosis of dementia or mild cognitive impairment underwent β-amyloid (18F-Florbetaben), tau (18F-Flortaucipir), and fluorodeoxyglucose (18F-FDG) PET. The TBI cohort included 15 participants with mild, 16 with moderate, and nine with severe injury. β-Amyloid level was calculated using the Centiloid (CL) method and tau was measured by standardized uptake value ratios (SUVRs) using the cerebellar cortex as reference region. Analyses were adjusted for age and APOE-e4. The findings were validated in an independent cohort from the Department of Defense-Alzheimer's Disease Neuroimaging Initiative (DOD ADNI) study. There were no significant nor trending differences in β-amyloid or tau levels or 18F-FDG uptake between the TBI and control groups before and after controlling for covariates. The β-amyloid and tau findings were replicated in the DOD ADNI validation cohort and persisted when the Australian Imaging Biomarkers and Lifestyle study of aging-Veterans study (AIBL-VETS) and DOD ADNI cohorts were combined (114 TBI vs. 87 controls in total). In conclusion, no increase in the later life accumulation of the neuropathological markers of AD in veterans with a remote history of TBI was identified.

Abstract Multinucleated microglia have been observed in contexts associated with infection, inflammation, and aging. Though commonly linked to pathological conditions, the larger cell size of multinucleated microglia might enhance their phagocytic functions, potentially aiding in the clearance of brain debris and suggesting a reassessment of their pathological significance. To assess the phagocytic capacity of multinucleated microglia and its implications for brain debris clearance, we induced their formation by inhibiting Pyk2 activity using the pharmacological inhibitor PF-431396, which triggers cytokinesis regression. Multinucleated microglia demonstrate enhanced phagocytic function, as evidenced by their increased capacity to engulf β-amyloid (Aβ) oligomers. Concurrently, the phosphorylation of Pyk2, induced by Aβ peptide, was diminished upon treatment with a Pyk2 inhibitor (Pyk2-Inh, PF-431396). Furthermore, the increased expression of Lamp1, a lysosomal marker, with Pyk2-inh treatment, suggests an enhancement in proteolytic activity. In vivo, we generated an acute Alzheimer’s disease (AD) model by infusing Aβ into the brains of Iba-1 EGFP transgenic (Tg) mice. The administration of the Pyk2-Inh led to an increased migration of microglia toward amyloid deposits in the brains of Iba-1 EGFP Tg mice, accompanied by morphological activation, suggesting a heightened affinity for Aβ. In human microglia, lipopolysaccharide (LPS)-induced inflammatory responses showed that inhibition of Pyk2 signaling significantly reduced the transcription and protein expression of pro-inflammatory markers. These results suggest that Pyk2 inhibition can modulate microglial functions, potentially reducing neuroinflammation and aiding in the clearance of neurodegenerative disease markers. This highlights Pyk2 as a promising target for therapeutic intervention in neurodegenerative diseases.