Determining the mechanisms of the protective APOE3ch variant on Alzheimer's Disease pathologies

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Project Summary Alzheimer's Disease (AD) is a progressive neurodegenerative disease that is the most common cause of dementia among older adults, 65 years and older. AD is characterized by the presence of extracellular amyloid β plaques (Aβ), intracellular neurofibrillary tau tangles (NFTs), and brain-wide neuroinflammation. Many current therapeutics targeting either Aβ or tau development have not been successful; therefore, it is imperative to understand the mechanisms in which these pathological hallmarks interact and influence each other. Aβ plaques develop many years before disease onset and do not correlate with clinical symptoms like the spread of tau. Moreover, immunotherapy targeting amyloid has failed to show cognitive improvement despite the significant reduction in Aβ load. While NFT-like tau pathology can develop without the presence of Aβ, the introduction of Aβ fibrils significantly accelerates NFT formation, further highlighting the need to better understand their molecular interactions. Recently, a case study has identified a carrier of the familial AD PSEN1 E280A mutation with a rare mutation in APOE3 (APOE R136S or APOE3ch) that resulted in resistance to neurodegeneration along with reduced NFTs while still exhibiting an elevated amyloid plaque load in the brain. The R136S mutation is located in a region of APOE known to have a role in binding to lipoprotein receptors and heparan sulfate proteoglycan (HSPGs), which have been suggested to promote amyloid-β aggregation and neuronal uptake of extracellular tau. Therefore, the APOE3ch mutation provides a unique interface to study the interaction between Aβ and tau. To that end, we have developed a novel ApoEch mouse model to be crossed with two different mouse models of amyloid and tau, 5xFAD and PS19, respectively. Thus, I propose to 1) Examine the protective effect of the ApoEch mutation in reducing tau pathology and rescuing neurodegeneration in PS19 mice, and 2) Assess the protective effect of the ApoEch mutation in dampening Aβ-associated plaque pathology and inflammation in 5xFAD mice. Collectively, this proposal will elucidate the role of this unique mutation in the development and manifestation of both Aβ and tau pathologies in mice.