Alzheimer's Disease Patients Research Articles

Ovariectomy and High Fat-Sugar-Salt Diet Induced Alzheimer's Disease/Vascular Dementia Features in Mice.

While the vast majority of Alzheimer's disease (AD) is non-familial, the animal models of AD that are commonly used for studying disease pathogenesis and development of therapy are mostly of a familial form. We aimed to generate a model reminiscent of the etiologies related to the common late-onset Alzheimer's disease (LOAD) sporadic disease that will recapitulate AD/dementia features. Naïve female mice underwent ovariectomy (OVX) to accelerate aging/menopause and were fed a high fat-sugar-salt diet to expose them to factors associated with increased risk of development of dementia/AD. The OVX mice fed a high fat-sugar-salt diet responded by dysregulation of glucose/insulin, lipid, and liver function homeostasis and increased body weight with slightly increased blood pressure. These mice developed AD-brain pathology (amyloid and tangle pathologies), gliosis (increased burden of astrocytes and activated microglia), impaied blood vessel density and neoangiogenesis, with cognitive impairment. Thus, OVX mice fed on a high fat-sugar-salt diet imitate a non-familial sporadic/environmental form of AD/dementia with vascular damage. This model is reminiscent of the etiologies related to the LOAD sporadic disease that represents a high portion of AD patients, with an added value of presenting concomitantly AD and vascular pathology, which is a common condition in dementia. Our model can, thereby, provide a valuable tool for studying disease pathogenesis and for the development of therapeutic approaches.

Exploring the Neural Mechanisms of Mirrored-Self Misidentification in Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative condition that causes a range of cognitive disturbances, including mirror-self misidentification syndrome (MSM), in which patients cannot recognize themselves in a mirror. However, the mechanism of action of MSM is not precisely known. This study aimed to explore the possible neural mechanisms of action of MSM in AD using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). This study included 48 AD patients, 13 in the MSM group and 35 in the non-MSM group. The permeability of the blood-brain barrier (BBB) was quantitatively monitored by measuring the transfer rate (Ktrans) of the contrast agent from the vasculature to the surrounding tissue using DCE-MRI. The concentration of contrast agents in different brain regions was measured, and the Patlak model was used to calculate Ktrans. Ktrans values were compared between the left and right cerebral hemispheres in different brain areas between the MSM and non-MSM groups. Additionally, the difference in Ktrans values between mild and severe MSM was assessed. Logistic regression analysis was used to examine the risk factors for MSM. The Mann‒Whitney U test was used to compare two groups and revealed elevated Ktrans values in the left thalamus, left putamen, left globus pallidus, left corona radiata, and right caudate in the MSM group (p<0.05). Logistic regression analysis revealed that increased Ktrans values in the left putamen (OR=1.53, 95% CI=1.04, 2.26) and left globus pallidus (OR=1.54, 95% CI=1.02, 2.31) may be risk factors for MSM. After dividing MSM patients into mild and moderate-severe groups, the Ktrans values of the thalamus in the moderate-severe group were greater than those in the mild group (p<0.05). Our study revealed the relationship between BBB permeability and MSM in AD. MSM is associated with BBB breakdown in the left putamen and globus pallidus. The left putamen and globus pallidus may function in mirror self-recognition. Higher BBB permeability in the thalamus may reflect the severity of AD in MSM.

Diagnostic Value of Serum Apolipoprotein B100 Combined With Hippocampal Volume in Alzheimer's Disease.

To explore the diagnostic value of serum apolipoprotein B100 (Apo B100) combined with hippocampal volume in Alzheimer's disease (AD). A total of 59 AD patients and 59 healthy subjects were selected. The Mini-Mental State Examination (MMSE) was used for neuropsychological assessment. Blood glucose and serum lipid levels were detected by biochemical analyzer. Polymerase chain reaction (PCR) was used to detect apolipoprotein E (Apo E) ε3/ε4 genotypes in the plasma. Hippocampal volume was calculated using Slicer software. Independent-sample t test or Mann-Whitney U test were used to compare the levels of various indicators between the two groups. Spearman's correlation analysis was used to analyze the correlation between each level. The receiver operating characteristic curve (ROC) was plotted, and the area under the curve (AUC) was calculated to compare the diagnostic efficacy of individual and combined detection of serum Apo B100 levels and hippocampal volume in AD. Compared with the healthy control group, the levels of serum total cholesterol (TC), low-density lipoprotein (LDL), Apo B100, and plasma Apo E ε3/ε4 were higher in the AD group, and serum high-density lipoprotein (HDL) level was lower in the AD group (both p<0.05). The hippocampal volume in the AD group was lower than in the control group (p<0.01). The serum Apo B100 level was negatively correlated with MMSE score (r=-0.646), whereas hippocampal volume was positively correlated with MMSE score (r=0.630). ROC curve analysis showed that the AUC of the combined serum Apo B100 level and hippocampal volume for AD was higher than that of either alone (AUC=0.821, p<0.01). Serum Apo B100 level is elevated, and the hippocampal volume is reduced in AD patients. The combined detection of the two has a higher diagnostic efficiency for AD than other alone and has the potential to become an important indicator for the diagnosis of AD in the future.

Comprehending the Rationale for Repurposing Type 2 Diabetes Mellitus Medicines for Alzheimer's Disease Patients Via Gene Networks Studies and its Associated Molecular Pathways

Type 2 Diabetes Mellitus (T2DM) is a known risk factor for Alzheimer’s disease (AD). Several epidemiological studies have reported a pathological association between AD and T2DM and have declared AD as a comorbidity of T2DM making T2DM a major risk factor for AD. Impaired insulin signaling elevates the risk for AD development and this can result in neurodegeneration via Aβ formation or increased inflammation in response to intraneural β amyloid. Insulin resistance, impaired glucose, carbohydrate and protein metabolism, and mitochondrial dysfunction are some characteristics common to both AD and T2DM. These features appear much before the clinical examination of both neurodegenerative diseases. It has now become extremely crucial to know the events that appear in the prodromal phases of these neurodegenerative disorders that elevate neurodegeneration risk. This has given rise to the idea that medications designed to treat T2DM may also help to alter the pathophysiology of AD and maintain cognitive function. This review highlights the recent and past evidence that correlates AD and T2DM, focusing on the shared pathogenic processes, and then evaluates the numerous medications given at clinical stages for assessing their potential activity in AD. Few molecular processes and their associated genes, altered protein metabolism (IAPP, Fyn/ERK/S6), altered carbohydrate metabolism (GLUT1, GLUT3, GLUT4), Impaired Acetylcholine (Ach) Synthesis (ACHE, ChAT), altered cholesterol metabolism (APOE4) were some of the biological reasons which made T2DM drugs useful for AD at the molecular level. Additionally, an in-silico strategy explores and evaluates the efficiency of T2DM medications like metformin, insulin, thiazolidinediones, etc. for AD treatment. The gene receptors for these drugs in the human system were predicted to understand the molecular pathways followed by these receptors which are common in AD pathology.

Evaluating The Factors Affecting Mortality and Survival of the Patients Who Underwent Percutaneous Endoscopic Gastrostomy; The Short-term and Long-term Results

Summary Aim Percutaneous endoscopic gastrostomy (PEG) is a common minimally invasive technique performed in patients with oral feeding problems. The aim of the current study is to evaluate the associated factors that have an impact on the short- and long-term survival and mortality in these patients who received PEG tube placement. Materials and Methods The patients who underwent PEG placement between June 2020 and June 2023 are enrolled in the study. Mortality data was extracted from the National Death Registry database. Data regarding the demographics, indications of PEG, co-morbidities, length of hospital stay prior to PEG procedure, the need for mechanical ventilator support, body-mass index, serum levels of hemoglobin, leukocyte, albumin, and c-reactive protein are extracted retrospectively. Kaplan Meier and Cox regression analyses were used to evaluate the factors affecting survival. Results A total of 137 patients are enrolled in the study (71 female and 66 male). One-month mortality was 16.7% and overall mortality during a follow-up of 38 months was 51%. Survival was significantly higher in patients with motor neuron diseases than the patients with Alzheimer’s (p=0.036). Length of hospital stay before PEG placement and hemoglobin levels were found to have a significant impact on survival in Cox regression analysis (p=0.000, p=0,009). Conclusion Length of hospital stay before PEGplacement, need for mechanical ventilator support and hemoglobin levels were found significantly associated with survival. Higher mortality in Alzheimer's patients may indicate that indications of PEG should be re-evaluated in these patients.

Extraction of In-Cell β-Amyloid Fibrillar Aggregates for Studying Molecular-Level Structural Propagations Using Solid-State NMR Spectroscopy.

Molecular-level structural polymorphisms of β-amyloid (Aβ) fibrils have recently been recognized as pathologically significant. High-resolution solid-state nuclear magnetic resonance (ssNMR) spectroscopy has been utilized to study these structural polymorphisms, particularly in ex-vivo fibrils seeded from amyloid extracts of post-mortem brain tissues of Alzheimer's disease (AD) patients. One unaddressed question in current ex-vivo seeding protocol is whether fibrillation from exogenous monomeric Aβ peptides, added to the extracted seeds, can be quantitatively suppressed. Addressing this issue is critical because uncontrolled fibrillation could introduce biased molecular structural polymorphisms in the resulting fibrils. Here, we present a workflow to optimize the key parameters of ex-vivo seeding protocols, focusing on the quantification of amyloid extraction and the selection of exogenous monomeric Aβ concentrations to minimize nonseeded fibrillation. We validate this workflow using three structurally different 40-residue Aβ (Aβ40) fibrillar seeds, demonstrating their ability to propagate their structural features to exogenous wild-type Aβ40.

Electrochemiluminescence biosensor for P-tau217 based on target-induced change of the steric hindrance effect of an antibody-modified electrode

Tau protein extensively phosphorylated at threonine 217 (p-tau217), has emerged with significant potential for initial clinical identification of Alzheimer’s disease (AD). In this study, a simple but sensitive electrochemiluminescence (ECL) immunosensor was designed for p-tau217 detection based on antigen–antibody specific binding to modulate the spatial hindrance of the gold electrode interface. Silica nanoparticles doped with ruthenium bipyridine (Ru@SiO2 NPs) were used as the ECL indicator. The p-tau217 monoclonal antibody was initially fixed onto the gold electrode surface, selectively capturing the p-tau217 protein, which subsequently increased the steric hindrance of the electrode. This process allowed for a decreased amount of Ru@SiO2 to access the electrode surface, which resulted in the relatively low ECL intensity being detected. The variation in ECL intensity exhibited a strong linear correlation with the logarithm of the target concentration, spanning from 1 pg/mL to 100 ng/mL, and a detection limit of 0.178 pg/mL was achieved. The proposed approach was effectively implemented to detect target in the serum of AD patients, and it delivered satisfactory outcomes.

Explainability of CNN-based Alzheimer's disease detection from online handwriting.

With over 55 million people globally affected by dementia and nearly 10 million new cases reported annually, Alzheimer's disease is a prevalent and challenging neurodegenerative disorder. Despite significant advancements in machine learning techniques for Alzheimer's disease detection, the widespread adoption of deep learning models raises concerns about their explainability. The lack of explainability in deep learning models for online handwriting analysis is a critical gap in the literature in the context of Alzheimer's disease detection. This paper addresses this challenge by interpreting predictions from a Convolutional Neural Network applied to multivariate time series data, generated by online handwriting data associated with continuous loop series handwritten on a graphical tablet. Our explainability methods reveal distinct motor behavior characteristics for healthy individuals and those diagnosed with Alzheimer's. Healthy subjects exhibited consistent, smooth movements, while Alzheimer's patients demonstrated erratic patterns marked by abrupt stops and direction changes. This emphasizes the critical role of explainability in translating complex models into clinically relevant insights. Our research contributes to the enhancement of early diagnosis, providing significant and reliable insights to stakeholders involved in patient care and intervention strategies. Our work bridges the gap between machine learning predictions and clinical insights, fostering a more effective and understandable application of advanced models for Alzheimer's disease assessment.

Cell-type-specific mapping of enhancers and target genes from single-cell multimodal data.

Mapping enhancers and target genes in disease-related cell types has provided critical insights into the functional mechanisms of genetic variants identified by genome-wide association studies (GWAS). However, most existing analyses rely on bulk data or cultured cell lines, which may fail to identify cell-type-specific enhancers and target genes. Recently, single-cell multimodal data measuring both gene expression and chromatin accessibility within the same cells have enabled the inference of enhancer-gene pairs in a cell-type-specific and context-specific manner. However, this task is challenged by the data's high sparsity, sequencing depth variation, and the computational burden of analyzing a large number of enhancer-gene pairs. To address these challenges, we propose scMultiMap, a statistical method that infers enhancer-gene association from sparse multimodal counts using a joint latent-variable model. It adjusts for technical confounding, permits fast moment-based estimation and provides analytically derived -values. In systematic analyses of blood and brain data, scMultiMap shows appropriate type I error control, high statistical power with greater reproducibility across independent datasets and stronger consistency with orthogonal data modalities. Meanwhile, its computational cost is less than 1% of existing methods. When applied to single-cell multimodal data from postmortem brain samples from Alzheimer's disease (AD) patients and controls, scMultiMap gave the highest heritability enrichment in microglia and revealed new insights into the regulatory mechanisms of AD GWAS variants in microglia.

Associations between the multitrajectory neuroplasticity of neuronavigated rTMS-mediated angular gyrus networks and brain gene expression in AD spectrum patients with sleep disorders.

The multifactorial influence of repetitive transcranial magnetic stimulation (rTMS) on neuroplasticity in neural networks is associated with improvements in cognitive dysfunction and sleep disorders. The mechanisms of rTMS and the transcriptional-neuronal correlation in Alzheimer's disease (AD) patients with sleep disorders have not been fully elucidated. Forty-six elderly participants with cognitive impairment (23 patients with low sleep quality and 23 patients with high sleep quality) underwent 4-week periods of neuronavigated rTMS of the angular gyrus and neuroimaging tests, and gene expression data for six post mortem brains were collected from another database. Transcription-neuroimaging association analysis was used to evaluate the effects on cognitive dysfunction and the underlying biological mechanisms involved. Distinct variable neuroplasticity in the anterior and posterior angular gyrus networks was detected in the low sleep quality group. These interactions were associated with multiple gene pathways, and the comprehensive effects were associated with improvements in episodic memory. Multitrajectory neuroplasticity is associated with complex biological mechanisms in AD-spectrum patients with sleep disorders. This was the first transcription-neuroimaging study to demonstrate that multitrajectory neuroplasticity in neural circuits was induced via neuronavigated rTMS, which was associated with complex gene expression in AD-spectrum patients with sleep disorders. The interactions between sleep quality and neuronavigated rTMS were coupled with multiple gene pathways and improvements in episodic memory. The present strategy for integrating neuroimaging, rTMS intervention, and genetic data provide a new approach to comprehending the biological mechanisms involved in AD.

Network Medicine Approach Unravels Endophenotype Signature in Alzheimer's Disease through Large-Scale Comparative Proteomics Analysis: Vascular Dysfunction as a Prime Example.

Alzheimer's disease (AD) is the most common neurodegenerative disease burdening public health. We proposed a network-based infrastructure to identify protein signatures for five AD pathological endophenotypes: amyloidosis, tauopathy, vascular dysfunction, lysosomal dysfunction, and neuroinflammation. We analyzed 23 proteomic data sets from AD patients and transgenic mouse models, using network proximity to measure associations between endophenotype modules and differentially expressed proteins (DEPs) in the integrated AD proteome. We focused on the vascular dysfunction signature with 21 DEPs by integrating RNA-seq, single-cell transcriptomics, GWAS, and literature. Experiments on APP/PS1 and MCAO models highlighted three proteins (SEPT5, SNAP25, STXBP1) as novel AD biomarker candidates. This study demonstrates a network medicine framework for deciphering endophenotype signatures in AD.

Investigation of amyloid‑β peptide production and clearance pathways in different stages of Alzheimer's disease.

Alzheimer's disease (AD) is an age‑related, progressive decline in cognitive ability. Accumulation and deposition of amyloid‑β (Aβ) is still the best‑known cause of AD that worsens over time. It is unclear whether the increase in Aβ production or the inefficiency of the degradation system causes the accumulation of β‑fibrils during AD development. This research investigated Aβ‑producing and clearance pathways in different stages of AD. For this purpose, patients were categorized into four experimental groups: patients with mild cognitive impairment, patients with moderate cognitive decline, patients with very severe cognitive decline, and healthy patients as control. Levels of Aβ‑40, soluble amyloid precursor protein beta (sAPPβ), matrix metalloproteinase‑9 (MMP‑9), matrix metalloproteinase‑3 (MMP‑3), neprilysin (NEP), angiotensin‑converting enzyme (ACE), and insulin‑degrading enzyme (IDE) were determined by ELISA kits and immunoblotting in serum samples. According to the results, the levels of Aβ‑40 and sAPPβ increased in AD patients from an early stage, and levels were maintained in progressive AD stages. MMP‑9 also increased in the early stage, but its content decreased with disease development. MMP‑3 was significantly higher in the three stages of AD compared to the control patients. However, IDE, NEP, and ACE enzymes as clearing systems decreased in all studied AD samples, with their reductions more remarkable in the middle and late stages. The results showed that multiple Aβ‑degrading enzymes such as NEP and IDE in AD patients decline as AD progresses, while Aβ‑40 and sAPPβ increased from the early stage of the disease. Therefore, it could be concluded that detection of the dementia phase is a critical step for therapeutic strategies.

MEDI1814 selectively reduces free Aβ42 in cerebrospinal fluid of non-clinical species and Alzheimer's disease patients.

Small molecules and antibodies are being developed to lower amyloid beta (Aβ) peptides. We describe MEDI1814, a fully human high-affinity monoclonal antibody selective for Aβ42, the pathogenic self-aggregating species of Aβ. MEDI1814 reduces free Aβ42 without impacting Aβ40 in the cerebrospinal fluid of rats and cynomolgus monkeys after systemic administration. MEDI1814 administration to patients with Alzheimer's disease (AD; n=57) in single or repeat doses up to 1800mg intravenously or 200mg subcutaneously was associated with a favorable safety and tolerability profile. No cases of amyloid-related imaging abnormalities were observed. Predictable dose-proportional changes in serum exposures for MEDI1814 were observed across cohorts. Cerebrospinal fluid (CSF) analysis demonstrated central nervous system penetration of MEDI1814. Pharmacodynamic data showed dose-dependent suppression of free Aβ42, increases in total (bound and free) Aβ42, but no change in total Aβ40 in CSF across doses. MEDI1814 offers a differentiated approach to impacting Aβ in AD via selective reduction of free Aβ42.

Exploring Caregiver Burden in Alzheimer's Disease: The Predictive Role Of Psychological Distress

Background Alzheimer's Disease [AD], the most prevalent form of dementia, is on the rise in terms of its prevalence. Individuals affected by this condition typically require extensive care across all aspects of daily living. The mental well-being of caregivers for those with dementia stands as a significant public concern. Therefore, the current study aimed to investigate the association between the burden of caregiving and the psychological distress experienced by family caregivers of individuals with AD. Methods This cross-sectional study employed a census method and involved the participation of 150 caregivers of Alzheimer's patients in Shahroud, Iran. To assess the eligibility of family caregivers, the inclusion criteria comprised minimal literacy in reading and writing and at least six months of care for an individual with AD.. Exclusion criteria included being a formal caregiver or employed in healthcare, having mental disorders, or using neuroleptic drugs among family caregivers. Data collection tools consisted of the Zarit Care Burden Inventory [ZBI] and Lovibond's Depression, Anxiety, and Stress Scale [DASS-21]. Information was gathered online and through self-reporting, followed by analysis using descriptive statistics [frequency, percentage, mean, and standard deviation], as well as inferential statistical tests [multivariate linear regression]. Results In this study, the mean scores for caregiver burden, anxiety, stress, and depression were 28.09 ±13.01, 4.50 ±4.53, 8.12 ±4.98, and 4.69 ± 4.86, respectively. The study's findings revealed that with each additional hour spent on daily patient care, the burden score for caregivers increased by 0.327 units [p=0.025, β=0.327]. Furthermore, for every one-unit rise in stress [p&lt;0.001, β=1.087] and depression scores [p=0.015, β=0.671], the burden score also increased by 1.087 and 0.671 units, respectively. Conclusion Caregivers of individuals with AD experienced notable levels of caregiving burden, particularly correlated with the duration of daily patient care and the manifestation of stress and depression symptoms. Hence, the study suggests the implementation of tailored interventions, such as psychoeducational programs, to provide vital support for these individuals.

Cerebrospinal Fluid Neurofilaments Light-Chain Differentiate Patients Affected by Alzheimer's Disease with Different Rate of Progression (RoP): A Preliminary Study.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and a leading cause of dementia. One major challenge for clinicians is accurately assessing the rate of disease progression (RoP) early in the diagnostic process, which is crucial for patient management and clinical trial stratification. This study evaluated the role of cerebrospinal fluid biomarkers-Aβ42, t-Tau, pTau, Neurogranin (Ng), and Neurofilament light-chain (NF-L)-in predicting RoP at the time of AD diagnosis. We included 56 AD patients and monitored cognitive impairment using MMSE scores at diagnosis and during six-month follow-up visits. RoP scores were calculated based on these assessments. Our correlation analyses revealed significant associations between RoP and pTau, Aβ42/Ng ratio, and NF-L levels. When patients were stratified by median RoP values into low-to-moderate (L-M: <2) and upper-moderate (U-M: >2) groups, those in the U-M group had notably higher CSF NF-L levels compared to the L-M group. Logistic regression analysis further demonstrated that elevated CSF NF-L levels were predictive of a faster RoP. These findings highlight the potential of CSF NF-L as a prognostic biomarker for rapid disease progression in AD. By identifying patients at risk for accelerated cognitive decline, CSF NF-L could significantly enhance early intervention strategies and improve patient management in clinical settings.

Involuntary Autobiographical Memory in Alzheimer's Disease: A Double-Edged Way of Remembering the Past?

Alzheimer's disease (AD) is characterized by severe memory alterations, affecting especially memories of personal past events. Until now, autobiographical memory impairments have been characterized using formal memory assessments, requiring patients to strategically and deliberately recall past events. However, contrary to this highly cognitively demanding mode of memory recall, autobiographical memories frequently come to mind unexpectedly based on automatic associative processes. The involuntary recall of personal memories is effortless and possibly represents a preserved way for AD patients to remember past events. This study aimed to investigate involuntary autobiographical memory in AD patients and compare the characteristics of these memories with those of healthy controls. Involuntary autobiographical memory was measured in 24 AD patients and 24 matched control participants using self-report measures. Participants were asked to report the frequency with which involuntary autobiographical memories were experienced in their daily life and to describe and self-assess one example of an involuntary memory. We showed that AD patients and control participants did not differ in terms of the frequency or subjective characteristics of their involuntary autobiographical memories in daily life, except for feelings of intrusiveness. Compared to control participants, AD patients reported their involuntary autobiographical memories as being more intrusive. In addition, more negative and vague involuntary autobiographical memories were associated with greater depressive symptoms. These findings open up a new avenue for research to better understand the extent to which involuntary autobiographical memory might be preserved in AD patients and why these memories may in turn become intrusive to patients.

Association of GLOD4 with Alzheimer's Disease in Humans and Mice.

Glyoxalase domain containing protein 4 (GLOD4), a protein of an unknown function, is associated with Alzheimer's disease (AD). Three GLOD4 isoforms are known. The mechanism underlying GLOD4's association with AD was unknown. To assess GLOD4's role in the central nervous system by studying GLOD4 isoforms expression in human frontal cerebral cortical tissues from AD patients and in brains of Blmh-/-5xFAD mouse AD model of AD. GLOD4 protein and mRNA were quantified in human and mouse brains by western blotting and RT-qPCR, respectively. Mouse brain amyloid-β (Aβ) was quantified by western blotting. Behavioral assessments of mice were performed by cognitive/neuromotor testing. Glod4 gene in mouse neuroblastoma N2a-APPswe cells was silenced by RNA interference and Glod4, Aβ precursor protein (Aβpp), Atg5, p62, and Lc3 proteins and mRNAs were quantified. GLOD4 mRNA and protein isoforms were downregulated in cortical tissues from AD patients compared to non-AD controls. Glod4 mRNA was downregulated in brains of Blmh-/-5xFAD mice compared to Blmh+/+5xFAD sibling controls, but not in Blmh-/- mice without the 5xFAD transgene compared to Blmh+/+ sibling controls. The 5xFAD transgene downregulated Glod4 mRNA in Blmh-/- mice of both sexes and in Blmh+/+ males but not females. Attenuated Glod4 was associated with elevated Aβ and worsened memory/sensorimotor performance in Blmh-/-5xFAD mice. Glod4 depletion in N2a-APPswe cells upregulated AβPP, and downregulated autophagy-related Atg5, p62, and Lc3 genes. These findings suggest that GLOD4 interacts with AβPP and the autophagy pathway, and that disruption of these interactions leads to Aβ accumulation and cognitive/neurosensory deficits.

Tau accumulation is cleared by the induced expression of VCP via autophagy.

Tauopathy, including frontotemporal lobar dementia and Alzheimer's disease, describes a class of neurodegenerative diseases characterized by the aberrant accumulation of Tau protein due to defects in proteostasis. Upon generating and characterizing a stable transgenic zebrafish that expresses the human TAUP301L mutant in a neuron-specific manner, we found that accumulating Tau protein was efficiently cleared via an enhanced autophagy activity despite constant Tau mRNA expression; apparent tauopathy-like phenotypes were revealed only when the autophagy was genetically or chemically inhibited. We performed RNA-seq analysis, genetic knockdown, and rescue experiments with clinically relevant point mutations of valosin-containing protein (VCP), and showed that induced expression of VCP, an essential cytosolic chaperone for the protein quality system, was a key factor for Tau degradation via its facilitation of the autophagy flux. This novel function of VCP in Tau clearance was further confirmed in a tauopathy mouse model where VCP overexpression significantly decreased the level of phosphorylated and oligomeric/aggregate Tau and rescued Tau-induced cognitive behavioral phenotypes, which were reversed when the autophagy was blocked. Importantly, VCP expression in the brains of human Alzheimer's disease patients was severely downregulated, consistent with its proposed role in Tau clearance. Taken together, these results suggest that enhancing the expression and activity of VCP in a spatiotemporal manner to facilitate the autophagy pathway is a potential therapeutic approach for treating tauopathy.

Stem Cells as a Novel Source for Regenerative Medicinal Applications in Alzheimer's Disease: An Update.

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by loss of the neurons, excessive accumulation of misfolded Aβ and Tau proteins, and degeneration of neural synapses, primarily occurring in the neocortex and the hippocampus regions of the brain. AD Progression is marked by cognitive deterioration, memory decline, disorientation, and loss of problem-solving skills, as well as language. Due to limited comprehension of the factors contributing to AD and its severity due to neuronal loss, even today, the medications approved by the U.S. Food and Drug Administration (FDA) are not precisely efficient and curative. Stem cells possess great potential in aiding AD due to their self-renewal, proliferation, and differentiation properties. Stem cell therapy can aid by replacing the lost neurons, enhancing neurogenesis, and providing an enriched environment to the pre-existing neural cells. Stem cell therapy has provided us with promising results in regard to the animal AD models, and even pre-clinical studies have shown rather positive results. Cell replacement therapies are potential curative means to treat AD, and there are a number of undergoing human clinical trials to make Stem Cell therapy accessible for AD patients. In this review, we aim to discuss the AD pathophysiology and varied stem cell types and their application.

The Kynurenine Pathway, Aryl Hydrocarbon Receptor, and Alzheimer's Disease.

Alzheimer's disease (AD) is the leading cause of dementia, mainly affecting elderly individuals. AD is characterized by β-amyloid plaques, abnormal tau tangles, neuronal loss, and metabolic disruptions. Recent studies have revealed the involvement of the kynurenine (KP) pathway and the aryl hydrocarbon receptor (AhR) in AD development. The KP pathway metabolizes tryptophan to produce neuroactive substances like kynurenine, kynurenic acid, and quinolinic acid. In AD, high levels of kynurenine and the neurotoxic quinolinic acid are associated with increased neuroinflammation and excitotoxicity; conversely, reduced levels of kynurenic acid, which acts as a glutamate receptor antagonist, compromise neuroprotection. Research has indicated elevated KP metabolites and enzymes in the hippocampus of AD patients and other tissues such as blood, cerebrospinal fluid, and urine. However, the finding that KP metabolites are AD biomarkers in blood, cerebrospinal fluid, and urine has been controversial. This controversy, stemming from the lack of consideration of the specific stage of AD, details of the patient's treatment, cognitive deficits, and psychiatric comorbidities, underscores the need for more comprehensive research. AhR, a ligand-activated transcription factor, regulates immune response, oxidative stress, and xenobiotic metabolism. Various ligands, including tryptophan metabolites, can activate it. Some studies suggest that AhR activation contributes to AD, while others propose that it provides neuroprotection. This discrepancy may be explained by the specific ligands that activate AhR, highlighting the complex relationship between the KP pathway, AhR activation, and AD, where the same pathway can produce both neuroprotective and harmful effects.