Basic Science and Pathogenesis.

Background: Prior studies have shown differences in the genetic etiology and clinical presentation of Alzheimer's Disease across populations. For example, for multiple genetic loci associated with AD, effect sizes can vary drastically between individuals of different ancestral backgrounds. Few investigations into differences in epigenetic features like DNA methylation have been conducted in AD, particularly in diverse individuals.

Basic Science and Pathogenesis.

Background: The Apoliproprotein E (APOE) e4 allele is the most significant genetic risk factor for late-onset Alzheimer disease (AD). However, the risk associated with the APOE e4 allele differs across populations with individuals of African ancestry having a reduced risk than individuals of European (EU) ancestry. Further, single-nuclei RNAseq analysis in autopsy samples from AD APOEε4 homozygotes with EU Local Ancestry (LA) had a significantly increased APOEε4 expression compared to those with African LA, particularly in astrocytes.

Basic Science and Pathogenesis.

Background: In the US, African Americans (admixed with African and European) followed by Hispanics (admixed with Amerindian, African, and European) are the most affected groups compared to non-Hispanic Whites (NHW). While genetic diversity and admixture play crucial roles in disease risk, the ancestry-specific mechanisms remain poorly understood with most AD-related studies focusing on NHW. Despite the recent field efforts to include genetically admixed populations, there continues to be a lack of functional studies in AD across the different cell types in these populations.

Basic Science and Pathogenesis.

Background: BIN1, the second strongest GWAS risk factor for late-onset Alzheimer's disease (AD), encodes a nucleocytoplasmic adaptor protein that plays many roles in multiple tissue and cell types. It is known that BIN1 can directly bind to tau in vitro, and neuronal BIN1 expression decreases in patients with AD. Accumulation of intracellular hyperphosphorylated tau is a hallmark pathogenic feature of AD and related tauopathies.

Basic Science and Pathogenesis.

Background: Microglia play significant roles in Alzheimer's disease (AD) pathophysiology. Current evidence suggests microglia may function in both protective and degenerative capacities, which has received little clarity from transcriptionally-characterised phenotypes uncovered from transgenic pathologies alone. BIN1 - the second-most significant risk gene for the development of late-onset AD (LOAD) - is expressed at high levels in neurons, oligodendrocytes and microglia.

Basic Science and Pathogenesis.

Background: Despite its high heritability, the genetic mechanisms influencing Alzheimer's Disease (AD), particularly in health disparity populations like African Americans (AA) and Hispanics (HI), are not fully understood. The lack of ancestral diversity in genetic datasets, notably in eQTL studies that associate genetic variation with gene expression, exacerbates these disparities. Our study seeks to address this gap by comparing the AD interactions of racially and ethnically diverse expression Quantitative Trait Loci (eQTL) effects to investigate the genetic influence on AD in underrepresented populations.

Basic Science and Pathogenesis.

Background: Tau accumulation, a hallmark of Alzheimer's disease, fuels cognitive decline and neuronal death. Our team identified FKBP51, a stabilizer of neurotoxic tau oligomers. Notably, FKBP51 levels increase with age and further in AD brains, where it is found associated with pathological tau.

Basic Science and Pathogenesis.

Background: We previously identified a 44-base pair deletion in (ATP-binding cassette sub-family A member 7) (ABCA7) that is significantly associated with Alzheimer's disease (AD) in African Americans (AA), producing a frameshift mutation resulting in a truncated protein (p.Arg578Alafs). ABCA7 is a lipid transporter across cellular membranes.

Basic Science and Pathogenesis.

Background: Genome-wide association studies (GWAS) in Alzheimer's disease (AD) are consistently discovering genetic variants linked to the risk of developing this neurodegenerative condition. However, the effect size of the shared associated loci varies across populations as well as each population can have unique associations. This phenomenon could be explained by ancestry-dependent changes in the genomic regulatory architecture (GRA) influencing the expression of these genes, similar to the effect of different local ancestry on the risk of AD in APOE4 carriers.

Basic Science and Pathogenesis.

Background: The "Recruitment and Retention for Alzheimer's Disease Diversity Genetic Cohorts in the ADSP (READD-ADSP)" is developing a resource to expand ancestral diversity in Alzheimer disease (AD) studies to dissect the genetic architecture of AD across different populations. In addition to US sites, READD-ADSP includes four US sites and nine countries in sub-Saharan Africa through the Africa Dementia Consortium (AfDC). The overall goal of READD-ADSP is to identify genetically driven targets in diverse groups including African Americans and Hispanic/Latinos in US, and Africans.

Clinical Manifestations.

Background: Over 13,000 individuals from both domestic and African sites will be collected for the READD-ADSP study. Adjudicating this number of individuals is challenging, so we evaluated knowledge-based decision tree algorithms to predict clinical diagnoses using nationally representative norms and standard cut-offs. Additional models were constructed using culturally adjusted cut-offs, domain average cut-offs, and exclusion of the Trail Making Test (TMT) which performed poorly.

FKBP51 overexpression in the corticolimbic system stabilizes circadian rhythms.

Circadian rhythm disruptions have been associated with a wide range of health issues and complications, including an increased risk of circadian rhythm sleep disorders (CRSDs). CRSDs are common among individuals who have been through a traumatic event, particularly in those who have post-traumatic stress disorder (PTSD). Allelic variations in the gene encoding for FK506-binding protein 51 (FKBP51) can increase the susceptibility for PTSD and other stress-related disorders following trauma.

Intrinsic Factors Behind the Long-COVID: V. Immunometabolic Disorders.

The complex link between COVID-19 and immunometabolic diseases demonstrates the important interaction between metabolic dysfunction and immunological response during viral infections. Severe COVID-19, defined by a hyperinflammatory state, is greatly impacted by underlying chronic illnesses aggravating the cytokine storm caused by increased levels of Pro-inflammatory cytokines. Metabolic reprogramming, including increased glycolysis and altered mitochondrial function, promotes viral replication and stimulates inflammatory cytokine production, contributing to illness severity.

Ageing drop by drop: Disturbance of the membrane-less organelle biogenesis as an aging hallmark.

Despite extensive research, the features associated with the aging phenotype are not all-inclusive and need to be updated on a regular basis to incorporate new findings. We propose to include the dysfunction of membrane-less organelle (MLO) as a new aging hallmark. Special scaffold proteins with a high degree of intrinsic disorder drive the formation of MLOs via the liquid-liquid phase separation (LLPS) process.

Two groups and three classes of the conserved structural organization of nucleophile and non-canonical ElbowFlankOxy networks in different superfamily proteins.

The nucleophile elbow is a well-known structural motif, which exists in proteins with catalytic triads and contains a catalytic nucleophile and the first node of an oxyanion hole. Here, we show that structural similarities of proteins with the nucleophile elbow extend beyond simple nucleophile elbow motifs. The motifs are incorporated into larger conserved structural organizations, the ElbowFlankOxy networks, incorporating motifs and flanking residues and networks of conserved interactions.

A Computational Approach to Characterize the Protein S-Mer Tyrosine Kinase (PROS1-MERTK) Protein-Protein Interaction Dynamics.

Protein S (PROS1) has recently been identified as a ligand for the TAM receptor MERTK, influencing immune response and cell survival. The PROS1-MERTK interaction plays a role in cancer progression, promoting immune evasion and metastasis in multiple cancers by fostering a tumor-supportive microenvironment. Despite its importance, limited structural insights into this interaction underscore the need for computational studies to explore their binding dynamics, potentially guiding targeted therapies.

Production of eukaryotic heliorhodopsins for structural analysis utilizing the LEXSY expression system.

Heliorhodopsins (HeRs) constitute a novel and distinct group of microbial rhodopsins, characterized by the inverted position of C- and N- termini relative to conventional Type I rhodopsins. The production of HeRs for structural and functional investigations has proven challenging, as evidenced by the structural elucidation of only two proteins and the functional characterization of a few others to date. Notably, no eukaryotic HeRs have been reported thus far.

Effects of the Amyotrophic Lateral Sclerosis-related Q108P Mutation on the Structural Ensemble Characteristics of CHCHD10.

Introduction: The Q108P pathological variant of the mitochondrial Coiled-Coil-Helix-- Coiled-Coil-Helix Domain-Containing Protein 10 (CHCHD10) has been implicated in amyotrophic lateral sclerosis (ALS). Both the wild-type and CHCHD10Q108P proteins exhibit intrinsically disordered regions, posing challenges for structural studies with conventional experimental tools.

Method: This study presents the foundational characterization of the structural features of CHCHD10Q108P and compares them with those of the wild-type counterpart.