Biology and Pathobiology of APOE in Aging and Alzheimer's Disease 2.0
Funded Grant
Overview
Affiliation
View All
Overview
description
SUMMARY/ABSTRACT (OVERALL) The overarching goal of this U19 renewal application is to comprehensively understand the molecular mechanisms underlying that protective variants of apolipoprotein E (APOE) prevent Alzheimer’s disease (AD) development to inform therapeutic strategies for age-related cognitive decline. The ε4 allele of the APOE gene (APOE4) is the strongest genetic risk factor for AD, while the ε2 allele is protective compared to the common ε3 allele. The recent game changing findings in the APOE research is that rare APOE coding variants such as APOE3 R136S “Christchurch” variant in N-terminal domain and APOE3 V236E “Jacksonville” variant and APOE4 R251G in C-terminal domain induce protective effects against AD. Thus, we propose an APOE cascade hypothesis for protective mechanisms that APOE protective variants in the N-terminal and C-terminal domains differently and commonly ameliorate gain-of-toxic functions of APOE by modulating their biophysical and biochemical properties including APOE aggregation, lipidation, and receptor binding, which lead to functional protective effects on cellular homeostasis thereby mitigating pathological conditions relevant to age-related cognitive decline and AD. Towards this, we have assembled a multi-disciplinary team to synergize expertise and resources across multiple institutions. By integrating four interactive Projects (Project 1: Deciphering the Structural and Biochemical Properties of APOE Protective Variants, Project 2: APOE protective variants and Alzheimer’s disease pathologies, Project 3: Impact of APOE protective variants on cerebrovascular damage, Project 4: Genetic modifiers for APOE-associated Alzheimer’s disease pathogenesis) and five robust Cores (Core A: Administrative Core, Core B: Human Biospecimen Core, Core C: Human iPSC Core, Core D: Muti- omics Core, Core E: Bioinformatics, Biostatistics and Data Management Core), we will create a nexus for APOE- related aging research, sharing knowledge, expertise and resources with the broader scientific community. In Aim 1, we will reveal the structure of protective APOE variants and address their biochemical and biophysical property differences. In Aim 2, we will determine how APOE protective variants modulate AD- and VCID-related pathologies. In Aim 3, we will address how APOE protective variants influence mixed pathologies and biomarker profiles in aging and AD. In Aim 4, we will investigate the molecular mechanisms mediated by APOE protective variants through the spatial and single cell multi-omics approaches. In Aim 5, we will serve as a nucleus for the APOE research community, and promote translational efforts by nominating mechanism-based, APOE-targeted therapies. Together, our U19 program continues to serve as a high-powered engine for APOE research to accelerate the discovery and to promote translation by interacting with academic and industry partners for APOE- targeted therapy for age-related neurodegenerative diseases.
SUMMARY/ABSTRACT (PROJECT 2) Alzheimer’s disease (AD) is marked by extracellular aggregation of amyloid-β (Aβ) peptides into amyloid plaques and aggregation of intracellular, aggregated and hyperphosphorylated tau protein. In AD, Aβ appears to drive tau pathology. The progressive accumulation of tau significantly correlates with neuronal/synaptic loss, regional brain atrophy, and neurodegeneration. Aβ and tau pathology both result in increased microglial and astrocyte reactivity. Apolipoprotein E (APOE) is the strongest genetic risk factor for AD. There are three common APOE alleles in humans (APOEε2, APOEε3, and APOEε4) distinguished by single amino acid differences. One allele of APOE4 increases the risk of AD by ~4-fold and two alleles of APOE4 increase AD risk by ~12-fold relative to the most common allele, APOE3. APOE2 decreases the risk of developing AD. APOE influences Aβ aggregation into fibrillar plaques in the order APOE4>APOE3>APOE2. In mouse models, in addition to APOE effects on amyloid, APOE also strongly increases tau-dependent neurodegeneration, glial reactivity, and microglial endolysosomal lipid accumulation. APOE4 has the strongest effects. A rare APOE variant, the APOE3-R136S “Christchurch” variant (E3R136S), is associated with marked protection against amyloid-induced tau pathology, neurodegeneration, and cognitive impairment in a woman with an autosomal dominant PSEN1 mutation. Suggesting causation, we found in a mouse model of amyloid-induced tau seeding and spreading that E3R136S expression somewhat reduced amyloid but very strongly reduced Aβ-induced tau pathology compared to APOE3. Notably, protective variants such as E3R136S and APOE2 exhibit reduced affinity for APOE receptors, which may underlie a protective mechanism through decreased competition for receptor mediated clearance of proteins such as Aβ or tau or decreased uptake of potentially toxic lipids in APOE lipoproteins. Recently, protective variants for AD were described that are located in the C-terminal region of APOE. These include the APOE3-V236E “Jacksonville” (E3V236E) variant and the APOE4-R251G (E4R251G) variant. Since these C-terminal variants are unlikely to affect receptor binding, their protective effects may reveal a novel mechanism by which affecting APOE function can be leveraged to reduce AD-associated pathology and neurodegeneration. We hypothesize that C-terminal variants of APOE that reduce AD risk result in structural changes in APOE that promote increased cellular cholesterol/lipid efflux, decreased glial lysosomal lipids, and reduced APOE aggregation. This then results in reduced amyloid, amyloid-induced tauopathy, glial cell activation, and tau-mediated neurodegeneration. This hypothesis will be assessed in the following aims: Aim 1. To assess the effects of E4R251G and E3V236E on amyloid deposition and subsequent effects. Aim 2. To assess effects of E4R251G and E3V236E on tau pathology and neurodegeneration. Aim 3. To investigate the biochemical and structural alterations caused by E4R251G and E3V236E on lipidated and non-lipidated APOE lipoproteins and their interactions with other molecules.
