Alzheimer's Disease Progression Research Articles

Mitochondrial dysfunction in Alzheimer's disease: a key frontier for future targeted therapies.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, accounting for approximately 70% of dementia cases worldwide. Patients gradually exhibit cognitive decline, such as memory loss, aphasia, and changes in personality and behavior. Research has shown that mitochondrial dysfunction plays a critical role in the onset and progression of AD. Mitochondrial dysfunction primarily leads to increased oxidative stress, imbalances in mitochondrial dynamics, impaired mitophagy, and mitochondrial genome abnormalities. These mitochondrial abnormalities are closely associated with amyloid-beta and tau protein pathology, collectively accelerating the neurodegenerative process. This review summarizes the role of mitochondria in the development of AD, the latest research progress, and explores the potential of mitochondria-targeted therapeutic strategies for AD. Targeting mitochondria-related pathways may significantly improve the quality of life for AD patients in the future.

The Missing Link in Antiamyloid Therapy.

Alzheimer's disease (AD) impacts millions of elderly adults worldwide causing cognitive decline and severe deterioration of activities of daily life. The popular causal hypotheses for several decades include beta-amyloid (Aβ) deposition and tau hyperphosphorylation. AD research and more than 34% of clinical trials in AD are based on these two hypotheses. A phase-III clinical trial of lecanemab in early AD and mild cognitive impaired (MCI) patients reported a delay in cognitive decline of 27% over an 18-month treatment schedule. This multicenter trial found high specificity of lecanemab toward toxic protofibrils and subsequent clearance of beta-amyloid. There were, however, adverse events, which included cerebral edema and intracerebral hemorrhages in 23.1% of patients compared to 9.3% for those who received a placebo. Suboptimal clinical outcomes, brain volume loss, and adverse events in lecanemab treatment prompted a search for an alternative etiopathogenic explanation. Our research and others have focused on the oxidative stress (OS) hypothesis in AD. Autopsy studies have found significant depletion of the master antioxidant glutathione (GSH) in the hippocampal region, and is believed to be an early event in AD progression. Hippocampal GSH depletion is positively correlated with memory impairment. We have confirmed non-invasively with magnetic resonance spectroscopy (MRS) the depletion of GSH in patients with MCI and AD. We therefore propose a combinational therapy involving oral supplementation of gamma-glutamylcysteine (GGC), an early precursor of glutathione, to replenish brain GSH in addition to lecanemab, potentially to maximize desirable outcomes from combined therapeutic approach.

Mannose Promotes β-Amyloid Pathology by Regulating BACE1 Glycosylation in Alzheimer's Disease.

Hyperglycemia accelerates Alzheimer's disease (AD) progression, yet the role of monosaccharides remains unclear. Here, it is demonstrated that mannose, a hexose, closely correlates with the pathological characteristics of AD, as confirmed by measuring mannose levels in the brains and serum of AD mice, as well as in the serum of AD patients. AD mice are given mannose by intra-cerebroventricular injection (ICV)or in drinking water to investigate the effects of mannose on cognition and AD pathological progression. Chronic mannose overload increases β-amyloid (Aβ) burdens and exacerbates cognitive impairments, which are reversed by a mannose-free diet or mannose transporter antagonists. Mechanistically, single-cell RNA sequencing and metabolomics suggested that mannose-mediated N-glycosylation of BACE1 and Nicastrin enhances their protein stability, promoting Aβ production. Additionally, reduced mannose intake decreased BACE1 and Nicastrin stability, ultimately lowering Aβ production and mitigating AD pathology. this results highlight that high-dose mannose consumption may exacerbate AD pathogenesis. Restricting dietary mannose may have therapeutic benefits.

NR1D1 Inhibition Enhances Autophagy and Mitophagy in Alzheimer's Disease Models.

Alzheimer's disease (AD) is marked by extracellular beta-amyloid (Aβ) plaques and intracellular Tau tangles, leading to progressive cognitive decline and neuronal dysfunction. Impaired autophagy, a process by which a cell breaks down and destroys damaged or abnormal proteins and other substances, contributes to AD progression. This study investigated Nuclear Receptor Subfamily 1 Group D Member 1 (NR1D1) as a potential therapeutic target for modulating autophagy. We show that NR1D1 depletion significantly enhances autophagic flux and mitophagy in human cell lines as well as wildtype and AD Caenorhabditis elegans (C. elegans) models. Our findings revealed that NR1D1 knockdown increased autophagy markers and activated the proteins Sirtuin 1 (SIRT1) and CTSB cathepsin B (Cathepsin B), both linked to autophagy function. In 5 familial AD mutations (5xFAD) mice, Nr1d1 knockdown restored the expression level of autophagy markers. C. elegans experiments revealed that depletion of the worm ortholog of NR1D1, nhr-85, improved neuronal mitophagy, enhanced associative memory in amyloid-β models, and extended lifespan. These findings suggest NR1D1 as a promising therapeutic target for improving cellular autophagy mechanisms in AD.

Ghrelin Induces Ferroptosis Resistance and M2 Polarization of Microglia to Alleviate Neuroinflammation and Cognitive Impairment in Alzheimer's Disease.

Microglial polarization and ferroptosis are important pathological features in Alzheimer's disease (AD). Ghrelin, a brain-gut hormone, has potential neuroprotective effects in AD. This study aimed to explore the potential mechanisms by which ghrelin regulates the progression of AD, as well as the crosstalk between microglial polarization and ferroptosis.Mouse BV2 microglial cells and male mice were treated with beta-amyloid (Aβ) (1-42) to simulate the AD environment. Microglia ferroptosis was measured by detecting levels of ferroptosis-related proteins (SLC7A11, GPX4, FTL1, and FTH1), metabolic markers (ROS, MDA, GSH, SOD), and observing mitochondrial morphological changes. Microglial polarization was evaluated by measuring levels of inflammatory markers and surface markers. The impact of ghrelin on Aβ1-42-exposed microglia was assessed by coupling with the ferroptosis activator Erastin. Cognitive impairment in AD mice was evaluated through behavioral tests. Tissue staining was applied to determine neuronal damage.In Aβ1-42-exposed microglia, ghrelin upregulated the protein expression of SLC7A11, GPX4, FTL1 and FTH1, reduced ROS and MDA levels, and elevated GSH and SOD levels through the BMP6/SMAD1 pathway. Ghrelin alleviated mitochondrial structural damage. Additionally, ghrelin reduced levels of pro-inflammatory factors and CD86, while increasing levels of anti-inflammatory factors and CD206. Erastin reversed the effects of ghrelin on ferroptosis and phenotypic polarization in Aβ1-42-exposed microglia. In AD mice, ghrelin ameliorated abnormal behavior, neuroinflammation, and plaque deposition. Ghrelin attenuated iNOS/IBA1-positive expression and enhanced Arg-1/IBA1-positive expression in the hippocampus. Ghrelin induces microglial M2 polarization by inhibiting microglia ferroptosis, thereby alleviating neuroinflammation. Our results indicate that ghrelin may serve as a promising potential agent for treating cognitive impairment in AD.

From Plant to Pathway: Molecular Mechanisms of Ruscogenin in Preventing Amyloid-Beta Aggregation through Computational and Experimental Approaches.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, extracellular amyloid-β (Aβ) plaque accumulation, and intracellular neurofibrillary tangles. Recent efforts to find effective therapies have increased interest in natural compounds with multifaceted effects on AD pathology. This study explores natural compounds for their potential to mitigate AD pathology using molecular docking, ADME screening, and in vitro assays, with ruscogenin─a steroidal sapogenin from Ruscus aculeatus─emerging as a promising candidate. Ruscogenin, known for its antioxidant and anti-inflammatory properties, was investigated for its effects on Aβ aggregation, a critical process in AD progression. In vitro assays demonstrated that ruscogenin inhibits Aβ oligomerization at equimolar and higher molar ratios. Molecular dynamics (MD) simulations further revealed that ruscogenin targets aggregation-prone regions, reducing noncovalent interactions and the solvent-accessible surface area of Aβ aggregates. These effects were concentration-dependent, with higher concentrations yielding optimal inhibition, pointing to a multiphasic behavior in ruscogenin's modulation of Aβ aggregation. This study highlights ruscogenin's potential as a natural therapeutic agent for AD, capable of addressing both oxidative stress and inflammation. The findings lay the groundwork for further exploration of ruscogenin-based interventions and underscore the broader potential of natural compounds in AD treatment strategies.

Information Geometry and Manifold Learning: A Novel Framework for Analyzing Alzheimer's Disease MRI Data.

Background: Alzheimer's disease is a progressive neurological condition marked by a decline in cognitive abilities. Early diagnosis is crucial but challenging due to overlapping symptoms among impairment stages, necessitating non-invasive, reliable diagnostic tools. Methods: We applied information geometry and manifold learning to analyze grayscale MRI scans classified into No Impairment, Very Mild, Mild, and Moderate Impairment. Preprocessed images were reduced via Principal Component Analysis (retaining 95% variance) and converted into statistical manifolds using estimated mean vectors and covariance matrices. Geodesic distances, computed with the Fisher Information metric, quantified class differences. Graph Neural Networks, including Graph Convolutional Networks (GCN), Graph Attention Networks (GAT), and GraphSAGE, were utilized to categorize impairment levels using graph-based representations of the MRI data. Results: Significant differences in covariance structures were observed, with increased variability and stronger feature correlations at higher impairment levels. Geodesic distances between No Impairment and Mild Impairment (58.68, p<0.001) and between Mild and Moderate Impairment (58.28, p<0.001) are statistically significant. GCN and GraphSAGE achieve perfect classification accuracy (precision, recall, F1-Score: 1.0), correctly identifying all instances across classes. GAT attains an overall accuracy of 59.61%, with variable performance across classes. Conclusions: Integrating information geometry, manifold learning, and GNNs effectively differentiates AD impairment stages from MRI data. The strong performance of GCN and GraphSAGE indicates their potential to assist clinicians in the early identification and tracking of Alzheimer's disease progression.

Unveiling FOXO3's metabolic contribution to menopause and Alzheimer's disease.

The increasing prevalence of Alzheimer's disease (AD) calls for a comprehensive exploration of its complex etiology, with a focus on sex-specific vulnerability, particularly the heightened susceptibility observed in postmenopausal women. Neurometabolic alterations during the endocrine transition emerge as early indicators of AD pathology, including reduced glucose metabolism and increased amyloid-beta (Aβ) deposition. The fluctuating endocrine environment, marked by declining estradiol levels and reduced estrogen receptor beta (ERβ) activity, further exacerbates this process. In this context, here we explore the potential of forkhead box O3 (FOXO3) as a critical mediator linking metabolic disturbances to hormonal decline. We propose that FOXO3 plays a key role in the intersection of menopause and AD, given its dysregulation in both AD patients and postmenopausal women, modulating cellular metabolism through interactions with the AMPK/AKT/PI3K pathways. This relationship highlights the intersection between hormonal changes and increased AD susceptibility. This review aims to open a discussion on FOXO3's contribution to the metabolic dysregulation seen in menopause and its impact on the progression of AD. Understanding the functional role of FOXO3 in menopause-associated metabolic changes could lead to targeted therapeutic strategies, offering novel insights for managing for this condition.

Calcium signaling hypothesis: A non-negligible pathogenesis in Alzheimer's disease.

Alzheimer's disease (AD) presents a significant challenge to global healthcare systems, with an exacerbation by an aging population. Although the plethora of hypotheses are proposed to elucidate the underlying mechanisms of AD, from amyloid-beta (Aβ) accumulation and Tau protein aggregation to neuroinflammation, a comprehensive understanding of its pathogenesis remains elusive. Recent research has highlighted the critical role of calcium (Ca2+) signaling pathway in the progression of AD, indicating a complex interplay between Ca2+ dysregulation and various pathological processes. This review aims to consolidate the current understanding of the role of Ca2+ signaling dysregulation in AD, thus emphasizing its central role amidst various pathological hypotheses. We aim to evaluate the potential of the Ca2+ signaling hypothesis to unify existing theories of AD pathogenesis and explore its implications for developing innovative therapeutic strategies through targeting Ca2+ dysregulation. The review focuses on three principal concepts. First, the indispensable role of Ca2+ homeostasis in neuronal function and its disruption in AD. Second, the interaction between Ca2+ signaling dysfunction and established AD hypotheses posited that Ca2+ dysregulation is a unifying pathway. Third, the dual role of Ca2+ in neurodegeneration and neuroprotection, highlighting the nuanced effects of Ca2+ levels on AD pathology.

The Role of M1 and M2 in Modulating Ab Accumulation and Function

Alzheimer's disease is a neurodegenerative disorder characterized by progressive cognitive decline, memory loss, and the formation of amyloid-beta plaques and tau tangles in the brain. This chronic condition has no known cure, and its progression varies greatly between individuals, eventually leading to severe cognitive impairment, loss of independence, and death. Microglia, the primary immune cells in the central nervous system that serve as the brain's first line of defense, are central to Alzheimer's disease pathology. Microglia play an important role in the response to injury and infection, as well as the regulation of amyloid-beta levels. However, when amyloid-beta accumulates, it activates an inflammatory response via microglia. While this response is initially protective, it may become chronic, contributing to the neuroinflammation that worsens Alzheimers disease pathology. In this study, I wanted to isolate and investigate the specific effects of M1 and M2 macrophages in the brains of genetically modified mice. Using CRISPR technology, we developed mouse models with selective expression of M1 macrophages without M2, M2 macrophages without M1, and models with both macrophage types. Western blot analysis quantified the levels of amyloid-beta in these mice, revealing how microglial activity influences Alzheimer's disease progression. Our findings show that M1 macrophages primarily regulate amyloid-beta through inflammatory processes, which may increase amyloid-beta production, whereas M2 macrophages are essential for amyloid-beta clearance. These findings emphasize the importance of balancing M1 and M2 macrophage activity when treating Alzheimer's disease

Intranasal amyloid model of Alzheimer's disease - potential opportunities and challenges.

Amyloid beta 1-42 (Aβ1-42) peptide is one of the most studied disease-related amyloidogenic peptides implicated in the pathophysiology of Alzheimer's disease (AD). Despite significant scientific breakthroughs in the recent past, the existing non-transgenic animal models do not demonstrate accurate pathology of AD progression. This review has presented a concise mechanistic understanding of the intranasal amyloid-based animal model of AD, along with its advantages, challenges, and major limitations. Furthermore, discussions on how to combat these challenges to pave the road toward developing novel therapeutics for AD, have also been included. Preclinical exploration of repeated intranasal amyloid-beta exposure would certainly aid the translational development of a robust animal model of AD. This will also provide a better understanding of disease progression and pathology in the intranasal animal model.

The Dynamics of Cognitive Decline towards Alzheimer's Disease Progression: Results from ADSP-PHC's Harmonized Cognitive Composites.

Accurately assessing temporal order of cognitive decline across multiple domains is critical in Alzheimer's disease (AD). Existing literature presented controversial conclusions likely due to the use of a single cohort and different analytical strategies. Harmonized composite cognitive measures in memory, language and executive functions from 13 cohorts in the ADSP-PHC data are used. A novel double anchoring events-based sigmoidal mixed model was developed using time to the incident of AD diagnosis as the time scale. Decline in memory occurred before decline in language which was followed by the decline in executive function. Throughout the entire AD continuum, APOE- ε 4 non-carriers and non-Hispanic Whites showed better memory performance, respectively, in all three cognitive domains. Using harmonized data across multiple cohorts is the key to accurately characterizing the temporal order of AD biomarkers. Time to incident AD diagnosis should be used as the time scale for reproducibility purposes.

Astrocytes phenomics as new druggable targets in healthy aging and Alzheimer's disease progression.

For over a century after their discovery astrocytes were regarded merely as cells located among other brain cells to hold and give support to neurons. Astrocytes activation, "astrocytosis" or A1 functional state, was considered a detrimental mechanism against neuronal survival. Recently, the scientific view on astrocytes has changed. Accumulating evidence indicate that astrocytes are not homogeneous, but rather encompass heterogeneous subpopulations of cells that differ from each other in terms of transcriptomics, molecular signature, function and response in physiological and pathological conditions. In this review, we report and discuss the recent literature on the phenomic differences of astrocytes in health and their modifications in disease conditions, focusing mainly on the hippocampus, a region involved in learning and memory encoding, in the age-related memory impairments, and in Alzheimer's disease (AD) dementia. The morphological and functional heterogeneity of astrocytes in different brain regions may be related to their different housekeeping functions. Astrocytes that express diverse transcriptomics and phenomics are present in strictly correlated brain regions and they are likely responsible for interactions essential for the formation of the specialized neural circuits that drive complex behaviors. In the contiguous and interconnected hippocampal areas CA1 and CA3, astrocytes show different, finely regulated, and region-specific heterogeneity. Heterogeneous astrocytes have specific activities in the healthy brain, and respond differently to physiological or pathological stimuli, such as inflammaging present in normal brain aging or beta-amyloid-dependent neuroinflammation typical of AD. To become reactive, astrocytes undergo transcriptional, functional, and morphological changes that transform them into cells with different properties and functions. Alterations of astrocytes affect the neurovascular unit, the blood-brain barrier and reverberate to other brain cell populations, favoring or dysregulating their activities. It will be of great interest to understand whether the differential phenomics of astrocytes in health and disease can explain the diverse vulnerability of the hippocampal areas to aging or to different damaging insults, in order to find new astrocyte-targeted therapies that might prevent or treat neurodegenerative disorders.

Unlocking the Vitamin Puzzle: Investigating Levels in People With Alzheimer's Disease Versus Healthy Controls Through Systematic Review and Network Meta-Analysis.

The progression of Alzheimer's disease (AD) is intricately tied to the impairment of neurons, crucial for neurological functions. Despite extensive research, the precise mechanism underlying AD development remains elusive due to its multifaceted aetiology. Vitamin deficiency has emerged as a notable contributor to AD onset and progression, exerting a significant influence on brain function. To explore this link, we conducted a thorough review using PubMed, Web of Science and MEDLINE databases to gather literature on average vitamin concentrations in people with AD and healthy controls. Applying frequentist network meta-analysis techniques, we calculated standardised mean differences (SMDs) in vitamin concentrations between AD and control groups, both directly and indirectly. Our analysis, based on 67 articles, revealed statistically significant findings for various vitamins. Notably, vitamin C displayed the most substantial difference in average concentration between AD and control groups, supported by a high p-score of 0.92. Other vitamins that showed significant differences included vitamin D, folate, vitamin E, vitamin A and vitamin B12. Moreover, by considering alternative reference groups of vitamins, we derived indirect estimates, which further emphasised the role of vitamins in AD pathology. The ranking of vitamins based on their discrepancy in concentration between AD and control groups underscored the importance of vitamin C, followed by vitamin D, vitamin E, folate, vitamin A and vitamin B12. In conclusion, our comprehensive analysis highlights the potential significance of vitamin levels in understanding AD pathology. This underscores avenues for further research and potential therapeutic interventions targeting vitamin deficiencies in people with AD, potentially offering new strategies for managing the disease. Trial Registration: CRD42023447203.

Shattering the Amyloid Illusion: The Microbial Enigma of Alzheimer's Disease Pathogenesis-From Gut Microbiota and Viruses to Brain Biofilms.

For decades, Alzheimer's Disease (AD) research has focused on the amyloid cascade hypothesis, which identifies amyloid-beta (Aβ) as the primary driver of the disease. However, the consistent failure of Aβ-targeted therapies to demonstrate efficacy, coupled with significant safety concerns, underscores the need to rethink our approach to AD treatment. Emerging evidence points to microbial infections as environmental factors in AD pathoetiology. Although a definitive causal link remains unestablished, the collective evidence is compelling. This review explores unconventional perspectives and emerging paradigms regarding microbial involvement in AD pathogenesis, emphasizing the gut-brain axis, brain biofilms, the oral microbiome, and viral infections. Transgenic mouse models show that gut microbiota dysregulation precedes brain Aβ accumulation, emphasizing gut-brain signaling pathways. Viral infections like Herpes Simplex Virus Type 1 (HSV-1) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) may lead to AD by modulating host processes like the immune system. Aβ peptide's antimicrobial function as a response to microbial infection might inadvertently promote AD. We discuss potential microbiome-based therapies as promising strategies for managing and potentially preventing AD progression. Fecal microbiota transplantation (FMT) restores gut microbial balance, reduces Aβ accumulation, and improves cognition in preclinical models. Probiotics and prebiotics reduce neuroinflammation and Aβ plaques, while antiviral therapies targeting HSV-1 and vaccines like the shingles vaccine show potential to mitigate AD pathology. Developing effective treatments requires standardized methods to identify and measure microbial infections in AD patients, enabling personalized therapies that address individual microbial contributions to AD pathogenesis. Further research is needed to clarify the interactions between microbes and Aβ, explore bacterial and viral interplay, and understand their broader effects on host processes to translate these insights into clinical interventions.

Altered brain-ventricle coupling modes over Alzheimer's disease progression detected with fMRI.

The origins of resting-state functional MRI (rsfMRI) signal fluctuations remain debated. Recent evidence shows coupling between global cortical rsfMRI signals and cerebrospinal fluid inflow in the fourth ventricle, increasing during sleep and decreasing with Alzheimer's disease (AD) progression, potentially reflecting brain clearance mechanisms. However, the existence of more complex brain-ventricle coupling modes and their relationship to cognitive decline remains unexplored. Analyzing 599 minimally-preprocessed rsfMRI scans from 163 elderly participants across the AD spectrum, we identified distinct brain-ventricle coupling modes that differentiate across groups and correlate with cognitive scores. Beyond the known anti-phase coupling between global brain signals and ventricles -more frequent in cognitively normal controls- we discovered additional modes where specific brain areas temporarily align with ventricle signals. At the cortical level, these modes form canonical resting-state networks, such as the Default Mode Network, which occurs less in AD or the Frontoparietal Network, which correlates positively with memory scores. The direct link between ventricle and brain signals challenges the common practice of removing CSF components from rsfMRI analyses and questions the origin of cortical signal fluctuations forming functional networks, which may reflect region-specific fluid inflow patterns. These findings provide new insights into the relationship between brain clearance mechanisms and network dysfunction in neurodegenerative diseases.

Neuropathology-based approach reveals novel Alzheimer's Disease genes and highlights female-specific pathways and causal links to disrupted lipid metabolism: insights into a vicious cycle

Dementia refers to an umbrella phenotype of many different underlying pathologies with Alzheimer’s disease (AD) being the most common type. Neuropathological examination remains the gold standard for accurate AD diagnosis, however, most that we know about AD genetics is based on Genome-Wide Association Studies (GWAS) of clinically defined AD. Such studies have identified multiple AD susceptibility variants with a significant portion of the heritability unexplained and highlighting the phenotypic and genetic heterogeneity of the clinically defined entity. Furthermore, despite women’s increased susceptibility to dementia, there is a lack of sex-specific genetic studies and understanding of sex-specific background for the disorder. Here, we aim to tackle the heterogeneity of AD by specifically concentrating on neuropathological features and pursuing sex-specific analysis. We bring together 14 different genomic and neuropathology datasets (6960 individuals) and we integrate our GWAS findings with transcriptomic and phenotypic data aiming to also identify biomarkers for AD progression. We uncover novel genetic associations to AD neuropathology, including BIN1 and OPCML. Our sex-specific analysis points to a role for BIN1 specifically in women as well as novel AD loci including QRFPR and SGCZ. Post-GWAS analyses illuminate the functional and biological mechanisms underlying AD and reveal sex-specific differences. Finally, through PheWAS and Mendelian Randomization analysis, we identify causal links with AD neuropathology pointing to disrupted lipid metabolism, as well as impaired peripheral immune response and liver dysfunction as part of a vicious cycle that fuels neurodegeneration.

Tau mediates the reshaping of the transcriptional landscape toward intermediate Alzheimer's disease stages.

Recent research revealed that Tau plays critical roles in various neuronal functions. We previously demonstrated that destabilization and nuclear delocalization of Tau alter the expression of glutamatergic genes, mediating early neuronal damage. In this study, we discovered that changes in Tau availability are linked to global alterations in gene expression that affect multiple neuronal pathways. Comparison with the human temporal region showed that the Tau-dependent modulation of gene expression closely resembles the intermediate stages of Alzheimer's disease (AD) that precede the definitive pathological condition. Furthermore, we identified the chromatin remodeling pathway as being significantly affected by Tau in both our cellular model and AD brains, with reductions in heterochromatin markers. Our findings indicate that Tau is able to globally affect the neuronal transcriptome and that its subcellular unbalance changes gene expression in the intermediate stages of AD development. In addition, we found that the chromatin architecture is affected by Tau during the progression of AD. These results provide new insights into the molecular mechanisms underlying early stages of AD development and highlight the central role of Tau and the contribution of nuclear Tau in this process.

Extracellular domain of TREM2 possess two distinct ligand recognition sites: Insights from machine-learning guided docking and all-atoms molecular dynamics simulations.

The myeloid-specific triggering receptors expressed on myeloid cells 2 (TREM2) is a group of class I receptors expressed in brain microglia plays a decisive role in neurodegenerative diseases such as Alzheimer's disease (AD) and Nasu Hakola disease (NHD). The extracellular domain (ECD) of TREM2 interacts with a wide-range of ligands, yet the molecular mechanism underlying recognition of such ligands to this class I receptor remains underexplored. Herein, we undertook a systematic investigation for exploring the mode of ligand recognition in immunoglobulin-like ectodomain by employing both knowledge-based and machine-learning guided molecular docking approach followed by the state-of-the-art all atoms molecular dynamics (MD) simulations. Besides the known binding site formed by complementarity-determining regions (CDR) 1 and CDR2 loops, which enables the binding of different anionic ligands, our study identifies the presence of second binding site formed by β-strands towards the C-terminal end. We observe a dense network of hydrophobic contacts formed between the explored ligands and CDR loops and β-strands, specifically CDR1, CDR2, β-strand C', loop connecting β-strand D and E, and loop connecting β-strand E and F. Ligand binding in immunoglobulin-like ectodomain increases the conformational flexibility of CDR2 loop, thus most frequently observed pathogenic variants i.e. R47H and R62H in TREM2 may affect the development and progression of AD. Our knowledge-based and machine-learning guided docking and physics-based simulations study unveils deep insights into the endogenous ligand recognition by the positive surface ligand binding site and distant core site pave the way for exploration of other small molecules towards development of novel therapeutics against Alzheimer's disease.

APOE4, Alzheimer's and Periodontal Disease: A scoping review.

the ε4 allele of the apolipoprotein E gene (APOE4) is recognized as the primary genetic risk factor for Alzheimer's disease (AD) and has been associated with chronic inflammatory conditions, such as periodontal disease (PD). PD has been identified as having a potentiating effect that favors the development and progression of AD. This scoping review investigates the potential relationship between PD and AD through APOE4 METHODS: the Joanna Briggs Institute methodology was used. The search included articles published in PubMed and Embase, focusing on human studies, and excluding case series, in vitro studies, reviews, and animal studies. among the studies that evaluated the relationship between PD, APOE4, and AD, a correlation was identified between the gingival index and cognitive impairment in APOΕ4 carriers. Additionally, higher levels of apolipoprotein E4 were found in the crevicular fluid of patients with both AD and PD, compared to individuals without AD. APOE4 may link PD and AD through shared genetic variants, inflammatory pathways, and dyslipidemia, involving both peripheral and central pathways. More comprehensive studies are required to ascertain the relationship between PD, AD, and APOE4 more accurately, and to clarify whether these connections are causal or non-causal.