Targeting hippocampal amyloidogenesis with SV2A protein modulator levetiracetam

Abstract

Cerebral amyloid β (Aβ) proteostasis is compromised under neuronal overexcitation, long-term neuroinflammation and brain aging. Using the animal model of LPS-induced neuroinflammation we demonstrated that treatment with levetiracetam, a specific modulator of synaptic vesicle glycoprotein SV2A, rescues abnormal synaptic vesicle (SV) fusion and neurotransmitter release, decreasing elevated hippocampal APP levels in vivo. Therapy with levetiracetam upregulates the SV2A in hippocampus and restores the level of apolipoprotein E, involved in brain Aβ aggregation/clearance and resolution of inflammation. We demonstrated that oligomers of Aβ_1-42 and Aβ_1-40 peptides promote SV clustering, which reduces the rate and plateau level of subsequent homo- and heterotypic SNARE-mediated SV fusion. Oligomeric Aβ_1-42 lowered ΔpH gradient across the vesicular membrane, thus affecting their neurotransmitter storage capacity. In contrast, monomers of Aβ_1-42 and Aβ_1-40 had negligible impact on studied processes. Our data suggests that in the course of progression of neuroinflammation oligomeric forms of Aβ_1-42 and Aβ_1-40 can compromise the SV fusion machinery and that antiepileptic agent levetiracetam, acting on SV recycling and restricting overexcitation, is able to affect APP processing and Aβ generation within the hippocampus in vivo.

Keywords: Amyloid β; Apolipoprotein E; Hippocampus; Levetiracetam; Neuroinflammation; SV2A protein.