Levetiracetam prevents Aβ₄₂ production through SV2a-dependent modulation of App processing in Alzheimer's disease models.

ABSTRACT: In Alzheimer's disease (AD), amyloid-beta (Aβ) peptides are produced by proteolytic cleavage of the amyloid precursor protein (APP), which can occur during synaptic vesicle (SV) cycling at presynapses. Precisely how amyloidogenic APP processing may impair presynaptic proteostasis and how to therapeutically target this process remains poorly understood. Using App knock-in mouse models of early Aβ pathology, we found proteins with hampered degradation accumulate at presynaptic sites. At this mild pathological stage, amyloidogenic processing leads to accumulation of Aβ₄₂ inside SVs. To explore if targeting SVs modulates Aβ accumulation, we investigated levetiracetam (Lev), a SV-binding small molecule drug that has shown promise in mitigating AD-related pathologies despite it

SUBMITTER: Rao NR 

PROVIDER: S-EPMC11565754 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature