Levetiracetam prevents Aβ production through SV2a-dependent modulation of APP processing in Alzheimer’s disease models

Amyloid-β (Aβ) peptides are a defining feature of Alzheimer’s disease (AD). These peptides are produced by the proteolytic processing of the amyloid precursor protein (APP), which can occur through the synaptic vesicle (SV) cycle. However, how amyloidogenic APP processing alters SV composition and presynaptic function is poorly understood. Using App knock-in mouse models of amyloid pathology, we found that proteins with impaired degradation accumulate at presynaptic sites together with Aβ 42 in the SV lumen. Levetiracetam (Lev) is a US Food and Drug Administration–approved antiepileptic that targets SVs and has shown therapeutic potential to reduce AD phenotypes through an undefined mechanism. We found that Lev lowers Aβ 42 levels by reducing amyloidogenic APP processing in an SV2a-dependent manner. Lev modified SV cycling and increased APP cell surface expression, which promoted its preferential processing through the nonamyloidogenic pathway. Stable isotope labeling combined with mass spectrometry confirmed that Lev prevents Aβ 42 production in vivo. In transgenic mice with aggressive amyloid pathology, electrophysiology and immunofluorescence confirmed that Lev restores SV cycling abnormalities and reduces synapse loss. Last, early Aβ pathology in brains from donors with Down syndrome was characterized by elevated presynaptic proteins. Together, these findings highlight the potential to prevent Aβ pathology before irreversible damage occurs.