Olivia DeGulis

Editor’s summary The accumulation of Aβ peptides in presynaptic terminals contributes to synaptic dysfunction in Alzheimer’s disease (AD). The antiepileptic, synaptic vesicle (SV) glycoprotein 2A–binding drug levetiracetam (Lev) has shown promise for the treatment of AD, potentially by targeting synaptic dysfunction, but the exact mechanism of action of Lev remains elusive. Here, Rao et al.

Abstract In Alzheimers 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.