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 A42. We also find that A42 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
Status | Finished |
---|---|
Effective start/end date | 9/1/15 → 4/30/22 |
Funding
- National Institute on Aging (5R01AG030142-10)
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.