PT  - JOURNAL ARTICLE
AU  - Nalini R. Rao
AU  - Jeffrey N. Savas
TI  - Levetiracetam treatment normalizes levels of the presynaptic endocytosis machinery and restores non-amyloidogenic APP processing in <em>App</em> knock-in mice
AID  - 10.1101/2021.02.22.432282
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.02.22.432282
4099  - http://biorxiv.org/content/early/2021/02/22/2021.02.22.432282.short
4100  - http://biorxiv.org/content/early/2021/02/22/2021.02.22.432282.full
AB  - Increasing evidence indicates that toxic amyloid-beta (Aβ) peptides, produced by sequential proteolytic cleavage of the Amyloid Precursor Protein (APP), induce neuronal circuit hyperexcitability in the early stages of Alzheimer’s disease (AD). As a result, treatments that modulate this early excitatory/inhibitory imbalance could act as potential AD therapies. Levetiracetam, an atypical antiepileptic drug, has garnered recent interest, despite the mechanism(s) of action remaining elusive. In this study, we set out to identify the pathways and mechanisms primarily affected by levetiracetam in diseased brains of amyloid pathology. Using the App knock-in mouse models and multiplexed TMT-quantitative mass spectrometry-based proteomic analysis to determine how levetiracetam affects the proteome, our findings demonstrate that levetiracetam treatment selectively normalizes levels of presynaptic endocytosis proteins and is capable of lowering Aβ42 levels by altering APP processing. These novel findings demonstrate a mechanism of action for how levetiracetam lowers Aβ42 production.Competing Interest StatementThe authors have declared no competing interest.Aβamyloid-betaAPPAmyloid Precursor ProteinADAlzheimer’s diseaseApp KIAPP knock-inβ-CTF/ α-CTFbeta/alpha carboxyl-terminal fragmentGOGene OntologyLEVlevetiracetamMSmass spectrometrySVsynaptic vesicleSV2Asynaptic vesicle glycoprotein 2ATMTtandem mass tagVEHvehicle