Molecular Neuropathology and Mechanisms of BACE1 Elevation in Alzheimer's Disease

Project: Research project

Project Details

Description

BACE1 is the -secretase enzyme that initiates A production and is a prime therapeutic target for AD. Drugs that inhibit BACE1 enzyme activity are in clinical trials for AD, however the safety and efficacy of these agents are unknown. Recent studies suggest that BACE1 inhibition may cause multiple neurological side effects. Thus, it is crucial to develop alternative therapeutic strategies that reduce BACE1 cleavage of APP without impairing essential BACE1 functions. We have shown that global BACE1 protein levels are markedly elevated in APP transgenic mouse and AD brains. Elevated BACE1 is concentrated within dystrophic axons and terminals surrounding amyloid plaques and is associated with increased generation of BACE1- cleaved APP fragments and A42. We also find that A42 causes increased resting [Ca2+]i and microtubule disruption in neurons. We hypothesize a feed-forward mechanism in which plaque-associated A causes axonal dystrophy, BACE1 accumulation, and accelerated A generation that drives AD progression. Elucidating the molecular and cellular mechanisms of dystrophic BACE1 elevation could lead to novel AD therapeutic strategies to normalize BACE1 levels and reduce peri-plaque A production, yet preserve BACE1 activity for essential functions and side effect mitigation. We hypothesize that A-induced Ca2+ influx into peri-plaque axons causes microtubule disruption, impaired axon transport, BACE1 accumulation, axonal dystrophy, and accelerated A generation and amyloid load. Our preliminary data show that A elevates resting [Ca2+]i in primary neurons via Ca2+-selective channels. Moreover, axons of A-treated primary neurons exhibit disrupted microtubules and impaired BACE1 axon transport. Peri-plaque dystrophic axons in 5XFAD mice also show elevated resting [Ca2+]i and disrupted microtubules. Using Ca2+ channel inhibitors or shRNA-AAVs, we will identify the channel(s) that mediates A-i
StatusFinished
Effective start/end date9/1/154/30/22

Funding

  • National Institute on Aging (5R01AG030142-10)

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