Sunday, November 24, 2024
11/24/2024
PROJECT SUMMARY The complexity and multifactorial nature of Alzheimer’s disease (AD) pose unique challenges for mechanistic studies and developing therapies. Emerging evidence strongly suggests that AD is a consequence of age- dependent neural network dysfunction in brain regions that mostly affect cognition, likely through interactive effects of multiple pathogenic factors, including apolipoprotein E (APOE), TAU, and amyloid-beta (Aβ). APOE4, the major genetic risk factor for late-onset AD, increases AD risk and lowers the age of disease onset in a gene dose-dependent manner, whereas APOE2 is a strongly protective genetic factor in late-onset AD. Two major pathological hallmarks of AD are intraneuronal tangles of hyperphosphorylated TAU and extracellular amyloid plaques of Aβ aggregates. In cell cultures and mouse models, APOE isoforms have Aβ- and TAU- dependent differential effects, and Aβ and TAU have APOE isoform-dependent effects, suggesting interactive roles of these factors in AD pathogenesis. However, almost all of these studies of APOE isoforms, Aβ, and TAU drew conclusions based on co-expression of mutant human APP, which is associated with early-onset but not late-onset AD, or mutant TAU, which is associated with frontotemporal dementia but not AD. Recently, a rare APOE variant, APOE3-R136S (APOE3-Christchurch), was found to protect against early-onset AD in a PSEN1-E280A carrier, further highlighting the importance of studying the rare variants of APOE in AD pathogenesis and protection. However, it is unknown whether the R136S mutation also protects against APOE4- driven effects in late-onset AD in the context of wildtype (WT) human TAU and APP. In this project, we propose to determine the potential protective effects of APOE-R136S on APOE4-driven neural network dysfunction, behavioral deficits, and pathologies, in the context of WT human TAU, WT APP with humanized Aβ1-42, or both, in novel mouse models of AD, and to explore the underlying cellular, molecular, and transcriptomic mechanisms. In Aim 1, we will determine the potential protective roles of APOE-R136S in novel AD mouse models expressing different human APOE isoforms and WT human TAU. In Aim 2, we will determine the potential protective roles of APOE-R136S in novel AD mouse models expressing different human APOE isoforms and WT APP with humanized Aβ1-42. In Aim 3, we will determine the potential protective roles of APOE-R136S in novel AD mouse models expressing different human APOE isoforms with both WT human TAU and WT APP with humanized Aβ1-42. The studies in this project will yield new insights into the multifactorial pathogenesis of AD, reveal cellular, molecular, and transcriptomic mechanisms underlying the protective roles of APOE-R136S in AD, and may identify novel targets for developing APOE-dependent therapies to treat or prevent AD.
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