A multicenter, randomized, double-blind, placebo-controlled ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of Posiphen in subjects with early Alzheimer's Disease.

BACKGROUND: Amyloid beta protein (Aß) is a treatment target in Alzheimer's Disease (AD). Lowering production of its parent protein, APP, has benefits in preclinical models. Posiphen, an orally administered small molecule, binds to an iron-responsive element in APP mRNA and decreases translation of APP and Aß. To augment human data for Posiphen, we evaluated safety, tolerability and pharmacokinetic and pharmacodynamic (PD) effects on Aß metabolism using Stable Isotope Labeling Kinetic (SILK) analysis. METHODS: Double-blind phase 1b randomized ascending dose clinical trial, at five sites, under an IRB-approved protocol. Participants with mild cognitive impairment or mild AD (Early AD) confirmed by low CSF Aß42/40 were randomized (within each dose arm) to Posiphen or placebo. Pretreatment assessment included lumbar puncture for CSF. Participants took Posiphen or placebo for 21-23 days, then underwent CSF catheter placement, intravenous infusion of 13C6-leucine, and CSF sampling for 36 h. Safety and tolerability were assessed through participant reports, EKG and laboratory tests. CSF SILK analysis measured Aß40, 38 and 42 with immunoprecipitation-mass spectrometry. Baseline and day 21 CSF APP, Aß and other biomarkers were measured with immunoassays. The Mini-Mental State Exam and ADAS-cog12 were given at baseline and day 21. RESULTS: From June 2017 to December 2021, 19 participants were enrolled, randomized within dose cohorts (5 active: 3 placebo) of 60 mg once/day and 60 mg twice/day; 1 participant was enrolled and completed 60 mg three times/day. 10 active drug and 5 placebo participants completed all study procedures. Posiphen was safe and well-tolerated. 8 participants had headaches related to CSF catheterization; 5 needed blood patches. Prespecified SILK analyses of Fractional Synthesis Rate (FSR) for CSF Aß40 showed no significant overall or dose-dependent effects of Posiphen vs. placebo. Comprehensive multiparameter modeling of APP kinetics supported dose-dependent lowering of APP production by Posiphen. Cognitive measures and CSF biomarkers did not change significantly from baseline to 21 days in Posiphen vs. placebo groups. CONCLUSIONS: Posiphen was safe and well-tolerated in Early AD. A multicenter SILK study was feasible. Findings are limited by small sample size but provide additional supportive safety and PK data. Comprehensive modeling of biomarker dynamics using SILK data may reveal subtle drug effects. TRIAL REGISTRATION: NCT02925650 on clinicaltrials.gov (registered on 10-24-2016).

Olfactory Dysfunction and Alzheimer's Disease: A Review.

 Alzheimer's disease is the most common cause of dementia, and it is one of the leading causes of death globally. Identification and validation of biomarkers that herald the onset and progression of Alzheimer's disease is of paramount importance for early reliable diagnosis and effective pharmacological therapy commencement. A substantial body of evidence has emerged demonstrating that olfactory dysfunction is a preclinical symptom of neurodegenerative diseases including Alzheimer's disease. While a correlation between olfactory dysfunction and Alzheimer's disease onset and progression in humans exists, the mechanism underlying this relationship remains unknown. The aim of this article is to review the current state of knowledge regarding the range of potential factors that may contribute to the development of Alzheimer's disease-related olfactory dysfunction. This review predominantly focuses on genetic mutations associated with Alzheimer's disease including amyloid-ß protein precursor, presenilin 1 and 2, and apolipoprotein E mutations, that may (in varying ways) drive the cellular events that lead to and sustain olfactory dysfunction.

Chlamydia pneumoniae in Alzheimer's disease pathology.

While recent advances in diagnostics and therapeutics offer promising new approaches for Alzheimer's disease (AD) diagnosis and treatment, there is still an unmet need for an effective remedy, suggesting new avenues of research are required. Besides many plausible etiologies for AD pathogenesis, mounting evidence supports a possible role for microbial infections. Various microbes have been identified in the postmortem brain tissues of human AD patients. Among bacterial pathogens in AD, Chlamydia pneumoniae (Cp) has been well characterized in human AD brains and is a leading candidate for an infectious involvement. However, no definitive studies have been performed proving or disproving Cp's role as a causative or accelerating agent in AD pathology and cognitive decline. In this review, we discuss recent updates for the role of Cp in human AD brains as well as experimental models of AD. Furthermore, based on the current literature, we have compiled a list of potential mechanistic pathways which may connect Cp with AD pathology.

Neuropathology, Neuroimaging, and Fluid Biomarkers in Alzheimer's Disease.

An improved understanding of the pathobiology of Alzheimer's disease (AD) should lead ultimately to an earlier and more accurate diagnosis of AD, providing the opportunity to intervene earlier in the disease process and to improve outcomes. The known hallmarks of Alzheimer's disease include amyloid-ß plaques and neurofibrillary tau tangles. It is now clear that an imbalance between production and clearance of the amyloid beta protein and related Aß peptides, especially Aß42, is a very early, initiating factor in Alzheimer's disease (AD) pathogenesis, leading to aggregates of hyperphosphorylation and misfolded tau protein, inflammation, and neurodegeneration. In this article, we review how the AD diagnostic process has been transformed in recent decades by our ability to measure these various elements of the pathological cascade through the use of imaging and fluid biomarkers. The more recently developed plasma biomarkers, especially phosphorylated-tau217 (p-tau217), have utility for screening and diagnosis of the earliest stages of AD. These biomarkers can also be used to measure target engagement by disease-modifying therapies and the response to treatment.

Precise prediction of cerebrospinal fluid amyloid beta protein for early Alzheimer's disease detection using multimodal data.

Alzheimer's disease (AD) constitutes a neurodegenerative disorder marked by a progressive decline in cognitive function and memory capacity. The accurate diagnosis of this condition predominantly relies on cerebrospinal fluid (CSF) markers, notwithstanding the associated burdens of pain and substantial financial costs endured by patients. This study encompasses subjects exhibiting varying degrees of cognitive impairment, encompassing individuals with subjective cognitive decline, mild cognitive impairment, and dementia, constituting a total sample size of 82 participants. The primary objective of this investigation is to explore the relationships among brain atrophy measurements derived from magnetic resonance imaging, atypical electroencephalography (EEG) patterns, behavioral assessment scales, and amyloid ß-protein (Aß) indicators. The findings of this research reveal that individuals displaying reduced Aß1-42/Aß-40 levels exhibit significant atrophy in the frontotemporal lobe, alongside irregularities in various parameters related to EEG frequency characteristics, signal complexity, inter-regional information exchange, and microstates. The study additionally endeavors to estimate Aß1-42/Aß-40 content through the application of a random forest algorithm, amalgamating structural data, electrophysiological features, and clinical scales, achieving a remarkable predictive precision of 91.6%. In summary, this study proposes a cost-effective methodology for acquiring CSF markers, thereby offering a valuable tool for the early detection of AD.

A multicenter, randomized, double-blind, placebo-controlled ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of Posiphen in subjects with Early Alzheimer's Disease.

Background: Amyloid beta protein (Aß) is a treatment target in Alzheimer's Disease (AD). Lowering production of its parent protein, APP, has benefits in preclinical models. Posiphen binds to an iron-responsive element in APP mRNA and decreases translation of APP and Aß. To augment human data for Posiphen, we evaluated safety, tolerability and pharmacokinetic and pharmacodynamic (PD) effects on Aß metabolism using Stable Isotope Labeling Kinetic (SILK) analysis. Methods: Double-blind phase 1b randomized ascending dose clinical trial, at five sites, under an IRB-approved protocol. Participants with mild cognitive impairment or mild AD (Early AD) with positive CSF biomarkers were randomized (within each dose arm) to Posiphen or placebo. Pretreatment assessment included lumbar puncture for CSF. Participants took Posiphen or placebo for 21-23 days, then underwent CSF catheter placement, intravenous infusion of 13C6-leucine, and CSF sampling for 36 hours. Safety and tolerability were assessed through participant reports, EKG and laboratory tests. CSF SILK analysis measured Aß40, 38 and 42 with immunoprecipitation-mass spectrometry. Baseline and day 21 CSF APP, Aß and other biomarkers were measured with immunoassays. The Mini-Mental State Exam and ADAS-cog12 were given at baseline and day 21. Results: From June 2017 to December 2021, 19 participants were enrolled, in dose cohorts (6 active: 2 placebo) of 60 mg once/day and 60 mg twice/day; 1 participant was enrolled and completed 60 mg three times/day. 10 active drug and 5 placebo participants completed all study procedures. Posiphen was safe and well-tolerated. 8 participants had headaches related to CSF catheterization; 5 needed blood patches. Prespecified SILK analyses of Fractional Synthesis Rate (FSR) for CSF Aß40 showed no significant overall or dose-dependent effects of Posiphen vs. placebo. Comprehensive multiparameter modeling of APP kinetics supported dose-dependent lowering of APP production by Posiphen. Cognitive measures and CSF biomarkers did not change significantly from baseline to 21 days in Posiphen vs placebo groups. Conclusions: Posiphen was safe and well-tolerated in Early AD. A multicenter SILK study was feasible. Findings are limited by small sample size but provide additional supportive safety and PK data. Comprehensive modeling of biomarker dynamics using SILK data may reveal subtle drug effects. Trial registration: NCT02925650 on clinicaltrials.gov.

Efficacy of Sailuotong on neurovascular unit in amyloid precursor protein/presenilin-1 transgenic mice with Alzheimer's disease.

OBJECTIVE: To discuss the influence of Sailuotong (, SLT) on the Neurovascular Unit (NVUs) of amyloid precursor protein (APP)/presenilin-1(PS1) mice and evaluate the role of gas supplementation in activating blood circulation during the progression of Alzheimer's disease (AD). METHODS: The mice were allocated into the following nine groups: (a) the C57 Black (C57BL) sham-operated group (control group), (b) ischaemic treatment in C57BL mice (the C57 ischaemic group), (c) the APP/PS1 sham surgery group (APP/PS1 model group), (d) ischaemic treatment in APP/PS1 mice (APP/PS1 ischaemic group), (e) C57BL mice treated with aspirin following ischaemic treatment (C57BL ischaemic + aspirin group), (f) C57BL mice treated with SLT following ischaemic treatment (C57BL ischaemic + SLT group), (g) APP/PS1 mice treated with SLT (APP/PS1 + SLT group), (h) APP/PS1 mice treated with donepezil hydrochloride following ischaemic treatment (APP/PS1 ischaemic + donepezil hydrochloride group) and (i) APP/PS1 mice treated with SLT following ischaemic treatment (APP/PS1 ischaemic + SLT group). The ischaemic model was established by operating on the bilateral common carotid arteries and creating a microembolism. The Morris water maze and step-down tests were used to detect the spatial behaviour and memory ability of mice. The hippocampus of each mouse was observed by haematoxylin and eosin (HE) and Congo red staining. The ultrastructure of NVUs in each group was observed by electron microscopy, and various biochemical indicators were detected by enzyme-linked immunosorbent assay (ELISA). The protein expression level was detected by Western blot. The mRNA expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: The results of the Morris water maze and step-down tests showed that ischemia reduced learning and memory in the mice, which were restored by SLT. The results of HE staining showed that SLT restored the pathological changes of the NVUs. The Congo red staining results revealed that SLT also improved the scattered orange-red sediments in the upper cortex and hippocampus of the APP/PS1 and APP/PS1 ischaemic mice. Furthermore, SLT significantly reduced the content of Aß, improved the vascular endothelium and repaired the mitochondrial structures. The ELISA detection, western blot detection and qRT-PCR showed that SLT significantly increased the vascular endothelial growth factor (VEGF), angiopoietin and basic fibroblast growth factor, as well as the levels of gene and protein expression of low-density lipoprotein receptor-related protein-1 (LRP-1) and VEGF in brain tissue. CONCLUSIONS: By increasing the expression of VEGF, SLT can promote vascular proliferation, up-regulate the expression of LRP-1, promote the clearance of Aß and improve the cognitive impairment of APP/PS1 mice. These results confirm that SLT can improve AD by promoting vascular proliferation and Aß clearance to protect the function of NVUs.

Current Insights of Nanocarrier-Mediated Gene Therapeutics to Treat Potential Impairment of Amyloid Beta Protein and Tau Protein in Alzheimer's Disease.

Alzheimer's disease (AD), is the major type of dementia and most progressive, irreversible widespread neurodegenerative disorder affecting the elderly worldwide. The prime hallmarks of Alzheimer's disease (AD) are beta-amyloid plaques (Aß) and neurofibrillary tangles (NFT). In spite of recent advances and developments in targeting the hallmarks of AD, symptomatic medications that promise neuroprotective activity against AD are currently unable to treat degenerating brain clinically or therapeutically and show little efficacy. The extensive progress of AD therapies over time has resulted in the advent of disease-modifying medications with the potential to alleviate AD. However, due to the presence of a defensive connection between the vascular system and the neural tissues known as the blood-brain barrier (BBB), directing these medications to the site of action in the degenerating brain is the key problem. BBB acts as a highly selective semipermeable membrane that prevents any type of foreign substance from entering the microenvironment of neurons. To overcome this limitation, the revolutionary approach of nanoparticle(NP)/nanocarrier-mediated drug delivery system has marked the era with its unique property to cross, avoid, or disrupt the defensive BBB efficiently and release the modified drug at the target site of action. After comprehensive data mining, this review focuses on the detailed understanding of different types of nanoparticle(NP)/nanocarrier-mediated drug delivery system like liposomes, micelles, gold nanoparticles(NP), polymeric NPs, etc. which have promising potential in carrying the desired drug(cargo) to the location in the degenerated brain thus mitigating the Alzheimer's disease.

Implementation of the neuro-glia-vascular unit through co-culture of adult neural stem cells and vascular cells and transcriptomic analysis of diverse Aß assembly types.

BACKGROUND: The blood-brain barrier (BBB) is a specialized layer between blood vessels and tissue in the brain, which is comprised of a neuro-glia-vascular (NGV) unit, thus play a vital role in various brain diseases. NEW METHOD: We developed the in vitro NGV units by co-culturing brain microvascular endothelial cells (BMECs; bEnd.3) and primary neural stem cells extracted from subventricular zone of adult mice. This approach was designed to mimic the RNA profile conditions found in the microvessels of a mouse brain and confirmed through various comparative transcriptome analyses. RESULTS: Optimal NGV unit development was achieved by adjusting cell density-dependent co-culture ratios. Specifically, the morphogenic development and neuronal association of astrocyte endfeet were well observed in the contact region with BMECs in the NGV unit. Through transcriptome analysis, we compared co-cultured bEnd.3/NSCs with monocultured bEnd.3 or NSCs and additionally compared them with previously reported mouse brain vascular tissue to show that this NGV unit model is a suitable in vitro model for neurological disease such as Alzheimer's disease (AD). COMPARISON WITH EXISTING METHOD(S): This in vitro NGV unit was formed from neural stem cells and vascular cells in the brain of adult mice, not embryos. It is very useful for studying brain disease mechanisms by identifying proteins and genes associated with diseases progress. CONCLUSIONS: We suggest that this simple in vitro NGV model is appropriate to investigate the relationship between BBB changes and pathological factors in the fields of neurovascular biology and cerebrovascular diseases including AD.

Dexmedetomidine mitigates neuroinflammation in an Alzheimer's disease mouse model via the miR-204-3p/FBXL7 signaling axis.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by neuroinflammation. Dexmedetomidine (Dex) is known for its neuroprotective properties in clinical settings. In this study, we investigated the potential of Dex in protecting against neuroinflammation in an AD mouse model induced by amyloid-beta (Aß) injection. First, in the AD mouse model, Aß injection were administered, and the model was confirmed through behavioral tests, including the Morris water maze and Y-maze. Neuroinflammatory states in Aß-injected mice were assessed using hematoxylin and eosin staining and enzyme-linked immunosorbent assay. Expression levels of microRNA (miR)-204-3p and F-box/LRR-repeat protein 7 (FBXL7) in mouse tissues were determined through real-time quantitative polymerase chain reaction and Western blot. The binding interaction between miR-204-3p and FBXL7 was elucidated using dual-luciferase analysis. Aß-injected mice exhibited cognitive impairment, neuroinflammation, and downregulated miR-204-3p. Upregulation of miR-204-3p reduced inflammatory infiltration and mitigated neuroinflammation in Aß-injected mice. Dex treatment reduced inflammation in hippocampal tissues of Aß-injected mice. Dex treatment upregulated miR-204-3p, leading to suppressed FBXL7 expression in tissues. Inhibition of miR-204-3p or overexpression of FBXL7 reversed the alleviating effect of Dex on neuroinflammation in Aß-injected mice. Overall, Dex increased miR-204-3p expression, resulting in the inhibition of FBXL7, and subsequently alleviated neuroinflammation in Aß-injected mice.

Roles of astrocytes and prions in Alzheimer's disease: insights from mathematical modeling.

We present a mathematical model that explores the progression of Alzheimer's disease, with a particular focus on the involvement of disease-related proteins and astrocytes. Our model consists of a coupled system of differential equations that delineates the dynamics of amyloid beta plaques, amyloid beta protein, tau protein, and astrocytes. Amyloid beta plaques can be considered fibrils that depend on both the plaque size and time. We change our mathematical model to a temporal system by applying an integration operation with respect to the plaque size. Theoretical analysis including existence, uniqueness, positivity, and boundedness is performed in our model. We extend our mathematical model by adding two populations, namely prion protein and amyloid beta-prion complex. We characterize the system dynamics by locating biologically feasible steady states and their local stability analysis for both models. The characterization of the proposed model can help inform in advancing our understanding of the development of Alzheimer's disease as well as its complicated dynamics. We investigate the global stability analysis around the interior equilibrium point by constructing a suitable Lyapunov function. We validate our theoretical analysis with the aid of extensive numerical illustrations.

Changes in Multiparametric Magnetic Resonance Imaging and Plasma Amyloid-Beta Protein in Subjective Cognitive Decline.

The association between plasma amyloid-beta protein (Aß) and subjective cognitive decline (SCD) remains controversial. We aimed to explore the correlation between neuroimaging findings, plasma Aß, and neuropsychological scales using data from 53 SCD patients and 46 age- and sex-matched healthy controls (HCs). Magnetic resonance imaging (MRI) was used to obtain neuroimaging data for a whole-brain voxel-based morphometry analysis and cortical functional network topological features. The SCD group had slightly lower Montreal Cognitive Assessment (MoCA) scores than the HC group. The Aß42 levels were significantly higher in the SCD group than in the HC group (p < 0.05). The SCD patients demonstrated reduced volumes in the left hippocampus, right rectal gyrus (REC.R), and right precentral gyrus (PreCG.R); an increased percentage fluctuation in the left thalamus (PerAF); and lower average small-world coefficient (aSigma) and average global efficiency (aEg) values. Correlation analyses with Aß and neuropsychological scales revealed significant positive correlations between the volumes of the HIP.L, REC.R, PreCG.R, and MoCA scores. The HIP.L volume and Aß42 were negatively correlated, as were the REC.R volume and Aß42/40. PerAF and aSigma were negatively and positively correlated with the MoCA scores, respectively. The aEg was positively correlated with Aß42/40. SCD patients may exhibit alterations in plasma biomarkers and multi-parameter MRI that resemble those observed in Alzheimer's disease, offering a theoretical foundation for early clinical intervention in SCD.

Arsenic Exposure and Amyloid Precursor Protein Processing: A Focus on Alzheimer's Disease.

BACKGROUND: Arsenic is present in above permissible safe limits in groundwater, soil, and food, in various areas of the world. This is increasing exposure to humankind and affecting health in various ways. Alternation in cognition is one among them. Epidemiological research has reflected the impact of arsenic exposure on children in the form of diminished cognition. AIMS: Considering this fact, the present study reviewed the impact of arsenic on amyloid precursor protein, which is known to cause one of the commonest cognitive disorders such as Alzheimer's disease. METHODS: The present study reviews the arsenic role in the generation of amyloid-beta from its precursor that leads to Alzheimer's disease through the published article from Pubmed and Scopus. DESCRIPTION: According to the findings, regular, long-term exposure to arsenic beginning in infancy changes numerous arsenic level-regulating regions in the rat brain, which are related to cognitive impairments. Arsenic also affects the BBB clearance route by increasing RAGE expression. Arsenic triggers the proamyloidogenic pathway by increasing APP expression and subsequently, its processing by ß-secretase and presenilin. Arsenic also affects mitochondrial dynamics, DNA repair pathway and epigenetic changes. The mechanism behind all these changes is explained in the present review article. CONCLUSION: A raised level of arsenic exposure affects the amyloid precursor protein, a factor for the early precipitation of Alzheimer's disease.

Supplementation of Medium-Chain Triglycerides Combined with Docosahexaenoic Acid Inhibits Amyloid Beta Protein Deposition by Improving Brain Glucose Metabolism in APP/PS1 Mice.

The deterioration of brain glucose metabolism predates the clinical onset of Alzheimer's disease (AD). Medium-chain triglycerides (MCTs) and docosahexaenoic acid (DHA) positively improve brain glucose metabolism and decrease the expression of AD-related proteins. However, the effects of the combined intervention are unclear. The present study explored the effects of the supplementation of MCTs combined with DHA in improving brain glucose metabolism and decreasing AD-related protein expression levels in APP/PS1 mice. The mice were assigned into four dietary treatment groups: the control group, MCTs group, DHA group, and MCTs + DHA group. The corresponding diet of the respective groups was fed to mice from the age of 3 to 11 months. The results showed that the supplementation of MCTs combined with DHA could increase serum octanoic acid (C8:0), decanoic acid (C10:0), DHA, and ß-hydroxybutyrate (ß-HB) levels; improve glucose metabolism; and reduce nerve cell apoptosis in the brain. Moreover, it also aided with decreasing the expression levels of amyloid beta protein (Aß), amyloid precursor protein (APP), ß-site APP cleaving enzyme-1 (BACE1), and presenilin-1 (PS1) in the brain. Furthermore, the supplementation of MCTs + DHA was significantly more beneficial than that of MCTs or DHA alone. In conclusion, the supplementation of MCTs combined with DHA could improve energy metabolism in the brain of APP/PS1 mice, thus decreasing nerve cell apoptosis and inhibiting the expression of Aß.

Fibrillization Process of Human Amyloid-Beta Protein (1-40) under a Molecular Crowding Environment Mimicking the Interior of Living Cells Using Cell Debris.

Molecular crowding environments play a crucial role in understanding the mechanisms of biological reactions. Inside living cells, a diverse array of molecules coexists within a volume fraction ranging from 10% to 30% v/v. However, conventional spectroscopic methods often face difficulties in selectively observing the structures of particular proteins or membranes within such molecularly crowded environments due to the presence of high background signals. Therefore, it is crucial to establish in vitro measurement conditions that closely resemble the intracellular environment. Meanwhile, the neutron scattering method offers a significant advantage in selectively observing target biological components, even within crowded environments. Recently, we have demonstrated a novel scattering method capable of selectively detecting the structures of targeted proteins or membranes in a closely mimicking intracellular milieu achieved utilizing whole-cell contents (deuterated-cell debris). This method relies on the inverse contrast matching technique in neutron scattering. By employing this method, we successfully observed the fibrillization process of human amyloid beta-protein (Aß 1-40) under a molecular crowding environment (13.1% w/v cell debris, Aß/cell debris = ~1/25 w/w) that closely mimics the interior of living cells. Aß protein is well known as a major pathogenic component of Alzheimer's disease. The present results combining model simulation analyses clearly show that the intracellular environment facilitates the potential formation of even more intricate higher-order aggregates of Aß proteins than those previously reported.

The Association of Alzheimer's Disease-related Blood-based Biomarkers with Cognitive Screening Test Performance in the Congolese Population in Kinshasa.

Background: Alzheimer's Disease (AD), the most common cause of dementia, poses a significant global burden. Diagnosis typically involves invasive and costly methods like neuroimaging or cerebrospinal fluid (CSF) biomarker testing of phosphorylated tau (p-tau) and amyloid-ß42/40 (Aß42/40). Such procedures are especially impractical in resource-constrained regions, such as the Democratic Republic of Congo (DRC). Blood-based biomarker testing may provide a more accessible screening opportunity. Objective: This study aims to examine if AD-related blood-based biomarkers are associated with cognitive test performance in the Congolese population, where limited research has been conducted. Methods: In this cross-sectional study of 81 Congolese individuals, cognitive assessments (Alzheimer's Questionnaire (AQ) and Community Screening Interview for Dementia (CSID)) distinguished dementia cases from controls. Blood draws were taken to assess p-tau 181 and Aß42/40 biomarkers. Relationships between the biomarkers and cognitive performance were analyzed using multiple linear regression models. Results: Lower plasma Aß42/40 was significantly associated with lower CSID scores and higher AQ scores, indicative of AD (p<0.001). These relationships were observed in healthy controls (CSID p=0.01, AQ p=0.03), but not in dementia cases. However, p-tau 181 did not exhibit significant associations with either measure. Factors such as age, sex, education, presence of APOE e4 allele, did not alter these relationships. Conclusion: Understanding relationships between AD-related screening tests and blood-biomarkers is a step towards utilization of blood-based biomarker tests as a screening tool for AD, especially in resource-limited regions. Further research should be conducted to evaluate blood biomarker test efficacy in larger samples and other populations.

Macrophage membrane-encapsulated nitrogen-doped carbon quantum dot nanosystem for targeted treatment of Alzheimer's disease: Regulating metal ion homeostasis and photothermal removal of ß-amyloid.

The abnormal aggregation of ß-amyloid protein (Aß) is a major contributor to Alzheimer's disease (AD). Cu2+ homeostasis imbalance can lead to the aggregation of Aß, resulting in cytotoxic oligomers and fibrous aggregates, causing neuroinflammation and nerve cell damage, ultimately leading to AD. In this study, we synthesized nitrogen-doped carbon quantum dot (CQD), and designed a macrophage membrane (RAW-M) encapsulated CQD nanosystem for the first time. The abundant nitrogen-containing groups on the surface of CQD effectively capture excess Cu2+ and inhibit rapid Aß aggregation. Additionally, the good photothermal properties of CQD dissolve the formed fiber precipitates under near-infrared light (NIR). In vitro and in vivo studies showed that the nanosystem significantly improved BBB permeability under laser irradiation, enhancing its ability to cross the BBB and overcome traditional anti-AD drug limitations. In vivo investigations conducted on APP/PS1 mice indicate that the nanosystem strongly reduced Aß deposition, mitigated neuroinflammation, and ameliorates deficits in learning and memory. Overall, our nanocarrier approach adjusts metal ion homeostasis, inhibits abnormal Aß aggregation, and uses excellent photothermal properties to depolymerize mature Aß fibrils to protect cells from Aß neurotoxicity, providing an effective strategy for Aß-targeted treatment of AD.

Vitreous Humor Biomarkers Reflect Pathological Changes in the Brain for Alzheimer's Disease and Chronic Traumatic Encephalopathy.

BACKGROUND: Patients with eye disease have an increased risk for developing neurodegenerative disease. Neurodegenerative proteins can be measured in the eye; however, correlations between biomarker levels in eye fluid and neuropathological diagnoses have not been established. OBJECTIVE: This exploratory, retrospective study examined vitreous humor from 41 postmortem eyes and brain tissue with neuropathological diagnoses of Alzheimer's disease (AD, n = 7), chronic traumatic encephalopathy (CTE, n = 15), both AD + CTE (n = 10), and without significant neuropathology (controls, n = 9). METHODS: Protein biomarkers i.e., amyloid-ß (Aß40,42), total tau (tTau), phosphorylated tau (pTau181,231), neurofilament light chain (NfL), and eotaxin-1 were quantitatively measured by immunoassay. Non-parametric tests were used to compare vitreous biomarker levels between groups. Spearman's rank correlation tests were used to correlate biomarker levels in vitreous and cortical tissue. The level of significance was set to α= 0.10. RESULTS: In pairwise comparisons, tTau levels were significantly increased in AD and CTE groups versus controls (p = 0.08 for both) as well as AD versus AD+CTE group and CTE versus AD+CTE group (p = 0.049 for both). Vitreous NfL levels were significantly increased in low CTE (Stage I/II) versus no CTE (p = 0.096) and in low CTE versus high CTE stage (p = 0.03). Vitreous and cortical tissue levels of pTau 231 (p = 0.02, r = 0.38) and t-Tau (p = 0.04, r = -0.34) were significantly correlated. CONCLUSION: The postmortem vitreous humor biomarker levels significantly correlate with AD and CTE pathology in corresponding brains, while vitreous NfL was correlated with the CTE staging. This exploratory study indicates that biomarkers in the vitreous humor may serve as a proxy for neuropathological disease.

γ-Secretase Inhibitors Selected by Molecular Docking, to Develop a New Drug Against Alzheimer's Disease.

Background: Alzheimer´s disease (AD) is one of the most common forms of dementia, is characterized by memory loss and cognitive impairment that affects more than 30 million people worldwide. The pathogenesis of Alzheimer's disease is primary driven by brain accumulation of the amyloid ß peptide generated from the amyloid-ß precursor protein (APP) via cleavages by ß- and γ-secretase. In this study, we propose an approach by molecular docking to select compounds as γ-secretase inhibitors for decreasing the APP generation. Methods: We selected potential γ-secretase inhibitors by molecular docking in the potential site between Asp257, Lue268, Asp385, Ile387, Phe388, and Leu432 amino acids in presenilin-1 (PS-1), using a chemical library of over 500,000 compounds. Results: Eight compounds (AZ1 - AZ8) were selected by molecular docking to develop γ-secretase inhibitors for decreasing the APP generation. Conclusions: AZ1 - AZ8 compounds could be interacting in the potential site between Asp257, Lue268, Asp385, Ile387, Phe388, and Leu432 amino acids in PS-1. These compounds could specifically interact in the binding pocket in PS-1 to prevent/decrease the APP generation, to develop a new drug against Alzheimer's disease.

LOTUS suppresses amyloid ß-induced dendritic spine elimination through the blockade of amyloid ß binding to PirB.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide but has no effective treatment. Amyloid beta (Aß) protein, a primary risk factor for AD, accumulates and aggregates in the brain of patients with AD. Paired immunoglobulin-like receptor B (PirB) has been identified as a receptor of Aß and Aß-PirB molecular interactions that cause synapse elimination and synaptic dysfunction. PirB deletion has been shown to suppress Aß-induced synaptic dysfunction and behavioral deficits in AD model mice, implying that PirB mediates Aß-induced AD pathology. Therefore, inhibiting the Aß-PirB molecular interaction could be a successful approach for combating AD pathology. We previously showed that lateral olfactory tract usher substance (LOTUS) is an endogenous antagonist of type1 Nogo receptor and PirB and that LOTUS overexpression promotes neuronal regeneration following damage to the central nervous system, including spinal cord injury and ischemic stroke. Therefore, in this study, we investigated whether LOTUS inhibits Aß-PirB interaction and Aß-induced dendritic spine elimination. METHODS: The inhibitory role of LOTUS against Aß-PirB (or leukocyte immunoglobulin-like receptor subfamily B member 2: LilrB2) binding was assessed using a ligand-receptor binding assay in Cos7 cells overexpressing PirB and/or LOTUS. We assessed whether LOTUS inhibits Aß-induced intracellular alterations and synaptotoxicity using immunoblots and spine imaging in a primary cultured hippocampal neuron. RESULTS: We found that LOTUS inhibits the binding of Aß to PirB overexpressed in Cos7 cells. In addition, we found that Aß-induced dephosphorylation of cofilin and Aß-induced decrease in post-synaptic density-95 expression were suppressed in cultured hippocampal neurons from LOTUS-overexpressing transgenic (LOTUS-tg) mice compared with that in wild-type mice. Moreover, primary cultured hippocampal neurons from LOTUS-tg mice improved the Aß-induced decrease in dendritic spine density. Finally, we studied whether human LOTUS protein inhibits Aß binding to LilrB2, a human homolog of PirB, and found that human LOTUS inhibited the binding of Aß to LilrB2 in a similar manner. CONCLUSIONS: This study implied that LOTUS improved Aß-induced synapse elimination by suppressing Aß-PirB interaction in rodents and inhibited Aß-LilrB2 interaction in humans. Our findings revealed that LOTUS may be a promising therapeutic agent in counteracting Aß-induced AD pathologies.