Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model.

TitleLevetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model.
Publication TypeJournal Article
Year of Publication2012
AuthorsSanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Ho K, Yu G-Q, Palop JJ, Mucke L
JournalProc Natl Acad Sci U S A
Volume109
Issue42
PaginationE2895-903
Date Published2012 Oct 16
ISSN1091-6490
KeywordsAlzheimer Disease, Amyloid beta-Protein Precursor, Analysis of Variance, Animals, Anticonvulsants, Blotting, Western, Cognition, Cognition Disorders, Electroencephalography, Humans, Immunohistochemistry, Maze Learning, Mice, Mice, Transgenic, Nerve Net, Piracetam, Synapses
Abstract

In light of the rising prevalence of Alzheimer's disease (AD), new strategies to prevent, halt, and reverse this condition are needed urgently. Perturbations of brain network activity are observed in AD patients and in conditions that increase the risk of developing AD, suggesting that aberrant network activity might contribute to AD-related cognitive decline. Human amyloid precursor protein (hAPP) transgenic mice simulate key aspects of AD, including pathologically elevated levels of amyloid-β peptides in brain, aberrant neural network activity, remodeling of hippocampal circuits, synaptic deficits, and behavioral abnormalities. Whether these alterations are linked in a causal chain remains unknown. To explore whether hAPP/amyloid-β-induced aberrant network activity contributes to synaptic and cognitive deficits, we treated hAPP mice with different antiepileptic drugs. Among the drugs tested, only levetiracetam (LEV) effectively reduced abnormal spike activity detected by electroencephalography. Chronic treatment with LEV also reversed hippocampal remodeling, behavioral abnormalities, synaptic dysfunction, and deficits in learning and memory in hAPP mice. Our findings support the hypothesis that aberrant network activity contributes causally to synaptic and cognitive deficits in hAPP mice. LEV might also help ameliorate related abnormalities in people who have or are at risk for AD.

DOI10.1073/pnas.1121081109
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID22869752
PubMed Central IDPMC3479491
Grant ListP50 AG023501 / AG / NIA NIH HHS / United States
R01 AG011385 / AG / NIA NIH HHS / United States
K23 AG038357 / AG / NIA NIH HHS / United States
RR18928-01 / RR / NCRR NIH HHS / United States
P30 NS065780 / NS / NINDS NIH HHS / United States
AG011385 / AG / NIA NIH HHS / United States
AG022074 / AG / NIA NIH HHS / United States
P01 AG022074 / AG / NIA NIH HHS / United States
AG023501 / AG / NIA NIH HHS / United States
NS065780 / NS / NINDS NIH HHS / United States
R37 AG011385 / AG / NIA NIH HHS / United States
C06 RR018928 / RR / NCRR NIH HHS / United States