Deciphering APOE function in Organoid and Mouse Models of Alzheimer's Disease
Julia Maeve Bonner1, Greg Sienski2, Yuan-Ta Lin1, Priyanka Narayan1, Li-Huei Tsai1,3 1Picower Institute for Learning and Memory; Massachusetts Institute of Technology 2Whitehead Institute for Biomedical Research 3Massachusetts Institute of Technology
Alzheimer's Disease (AD) is a widespread, progressive and fatal disease, characterized by the loss of memory and cognitive function associated in part with the accumulation of a protein fragment called beta-amyloid (Aβ). The ε4 allele of the APOE gene (APOE4), occurring in about 13.7% of the population, is the single strongest risk factor for late onset AD. Individuals with one APOE4 allele are 2-3 times more likely to develop AD, while those with two copies are up to 12 times more likely to develop AD. There is currently no cure for AD, and treatments are aimed solely at ameliorating symptoms and attenuating disease progression. Disruptions in endosomal and trans-Golgi network trafficking are associated with the formation of toxic Abeta species and endocytic dysfunction is implicated early in AD progression. Indeed, APOE4 appears to promote β-amyloidogenesis through the endosomal-lysosomal network, as well as contributing to AD pathogenesis through other pathways including tauopathy, defects in synaptic plasticity, lipid transport, mitochondrial function and neuroinflammation, among others. Despite the evident importance of APOE to AD onset and pathology, the mechanism by which APOE primarily contributes to AD, and the effect of APOE4 on trafficking are poorly understood. Previous research in yeast models of AD have suggested key pathways and molecules that may ameliorate AD phenotypes. Using both mouse models and human patient-derived tissue, including neural organoids, we are examining the effect of APOE4 on AD pathophysiology onset and progression and exploring the use of genetic and small molecule modifiers identified in yeast models to alleviate APOE4 related defects associated with AD.
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