S3-03-01: BACE1 levels are elevated in a rapid amyloid pathology transgenic mouse model of Alzheimer's disease

Abstract

BACE1 (β-secretase) initiates the production of β-amyloid (Aβ), the main constituent of amyloid plaques in Alzheimer's disease (AD). BACE1 levels are increased in AD brain, implying that elevated BACE1 levels may promote Aβ generation and AD. In addition, reduced glucose utilization occurs early in AD, suggesting that impaired energy metabolism might lead to AD pathogenesis. Also, BACE1 levels are elevated in Alzheimer's disease brain, suggesting a positive feedback mechanism in AD. To study the effects of aggressive amyloid deposition on BACE1 levels in vivo, we generated transgenic mice that overexpress APP with 3 familial AD (FAD) mutations (Swedish, Florida, London) and 2 FAD mutations in PS1 (M146L, L286V), which we call 5XFAD mice. These mutations act additively to increase Aβ42 production. Mice were then analyzed for effects on amyloid and BACE1 levels. Our recent work has demonstrated that impairment of energy metabolism via treatment with pharmacologic inhibitors of ATP production causes BACE1 levels to increase in the brains of an APP transgenic model of AD, the Tg2576 mouse. The elevated BACE1 levels in turn cause increased APP amyloidogenic processing, Aβ production, and amyloid plaque formation. These results suggest that impaired energy metabolism may play an important role in the early phases of AD pathogenesis. In addition, using a novel mono-specific anti-BACE1 antibody, we have shown that BACE1 levels are increased around the Aβ42 cores of amyloid plaques in AD and two APP transgenic mouse models: Tg2576 and 5XFAD mice. BACE1 levels are elevated in presynaptic neuronal structures (likely dystrophic neurites) that surround amyloid plaques, and BACE1 co-localizes with APP in these structures. Our results suggest that increased amyloidogenic processing of APP occurs in dystrophic neurites around plaques, thus exacerbating amyloid deposition. Taken together, our work is consistent with the hypothesis that impaired energy metabolism may lead to increased BACE1 levels and subsequent elevation of Aβ generation. Once amyloid plaques form, Aβ neurotoxicity causes BACE1 levels to increase further in dystrophic neurites around plaques, thus accelerating Aβ formation and plaque growth via a positive-feedback loop.