Targeting hippocampal amyloidogenesis with SV2A protein modulator levetiracetam
Biochemical pharmacology(2022)
摘要
Cerebral amyloid beta (A beta) 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 A beta aggregation/clearance and resolution of inflammation. We demonstrated that oligomers of A beta(1-42) and A beta(1-40) peptides promote SV clustering, which reduces the rate and plateau level of subsequent homo-and heterotypic SNARE-mediated SV fusion. Oligomeric A beta(1-42) lowered Delta pH gradient across the vesicular membrane, thus affecting their neurotransmitter storage capacity. In contrast, monomers of A beta(1-42) and A beta(1-40) had negligible impact on studied processes. Our data suggests that in the course of progression of neuroinflammation oligomeric forms of A beta(1-42) and A beta(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 A beta generation within the hippocampus in vivo.
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关键词
Neuroinflammation,Amyloid beta,Hippocampus,Levetiracetam,SV2A protein,Apolipoprotein E
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