Investigating the Role of Apolipoprotein E and Neuroinflammatory Modulation in Alzheimer's Disease

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease diagnosed today, characterized by significant cognitive decline with few disease-modifying options available. Molecular AD pathology consists of extracellular amyloid plaques subsequently followed by intracellular neurofibrillary tau tangles, both of which lead to substantial inflammation and degeneration. The gene encoding apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor of AD, known to seed amyloid plaques. Previous work has demonstrated that mouse Apoe-targeting siRNA induces a hyperinflammatory signature in 5xFAD mice, an AD model recapitulating human amyloid burden. This work uses therapeutically-relevant siRNA technology to probe the dual role of ApoE and neuroinflammation by targeting both Apoe and Jak1, a master regulator of interferon signaling relevant to destructive AD neuroinflammation. Although inflammatory signaling, primarily by microglia, plays an important role in clearing AD pathology, overactive inflammatory signaling is detrimental to the brain, leading to worsening degeneration. Therefore, we hypothesized that Jak1 modulation would reduce hyperactive inflammation while Apoe modulation would improve amyloid clearance. 5xFAD mice were treated with a single injection of Apoe and Jak1-targeting siRNAs over two months to evaluate molecular markers and amyloid pathology. Amyloid burden was significantly reduced in both Apoe and dual-targeting Apoe+Jak1 groups, demonstrating that JAK1 signaling is not required for microglial-mediated plaque clearance. This provides a proof-of-concept for further investigation of dual-targeting Apoe and Jak1 as a disease-modifying treatment option.