Endolysosomal Pathways in Alzheimer's Disease

Endosomal dysfunction is implicated in the pathogenesis of Alzheimer’s disease (AD). Variants in SORL1 encoding a receptor for the retromer complex (the master regulator of endosomal trafficking) has been strongly linked to AD. Disrupting the retromer-SORLA pathway mediated regulation of endosomal trafficking triggers AD’s molecular/cellular pathologies in various ways: i) disrupting the retromer-SORLA complex reduces glutamate receptor recycling to the surface of dendritic spines, triggering the early stages of the neurodegenerative process; ii) with SORLA as the intermediary, retromer traffics APP away from its amyloidogenic cleavage in early endosomes. Retromer core or SORLA depletion causes endosomal traffic jam and thereby enhancement of APP processing to Aß; iii) dysfunction of the retromer trafficking pathway, by depleting either SORLA or VPS26b, accelerates tau secretion; iv) a recent study showed that retromer dysfunction in neurons triggers morphological alterations that phenocopy microglia abnormalities observed in the AD brain, and that the microglial pathology can be partially rescued by neuronal retromer gene therapy. These studies provide a strong rationale to investigate the retromer-SORLA pathway as a functional druggable target to slow the course of AD by restoring endosomal function. A critical step for this is to identify individuals carrying pathogenic variants in SORL1 and other endosomal trafficking genes and characterize their (endo)phenotypic profiles including cognitive clinical course and AD biomarker profiles. The goal of this proposal is to determine which SORL1 variants and variants in other endosomal trafficking genes are truly pathogenic and may be valuable drug development candidates by identifying variant carriers in ADSP WGS data and assessing critical endophenotypes in these individuals including cognitive profiles and biofluidic biomarker profiles.

Intracellular trafficking of critical proteins is an important mechanistic pathway in the pathogenesis of Alzheimer’s disease (AD). A master regulator of intracellular endosomal trafficking is the retromer complex. An increasing number of studies indicate that the retromer may be a valuable functional druggable target to slow the course of AD, and a critical step for this is to identify individuals carrying pathogenic variants in retromer-related genes and characterize their (endo)phenotypic profiles including cognitive clinical course and AD biomarker profiles. The goal of this proposal is to determine which genetic variants in endosomal trafficking genes are truly pathogenic and may be valuable drug development candidates by identifying variant carriers in ADSP WGS data and assessing critical endophenotypes in these individuals including cognitive profiles and biofluidic biomarker profiles.