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

Proceedings of the National Academy of Sciences of the United States of America - Tập 109 Số 42 - 2012
Pascal E. Sanchez1,2, Lei Zhu1,2, Laure Verret3,1,2, Keith Vossel1,2, Anna G. Orr1,2, John R. Cirrito4, Nino Devidze2, Kaitlyn Ho2, Yu Gui2, Jorge J. Palop1,2, Lennart Mucke1,2
1Department of Neurology, University of California, San Francisco, CA 94158; and
2Gladstone Institute of Neurological Disease, San Francisco, CA 94158;
3Centre de Recherches sur la Cognition Animale - UMR5169
4Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110

Tóm tắt

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.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 109 Số 42

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