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

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.

Từ khóa


Tài liệu tham khảo

A Wimo, M Prince World Alzheimer Report 2010: The Global Economic Impact of Dementia (Alzheimer's Disease International, London), pp. 1–56 (2010).

10.1038/nn.2583

10.1016/j.cell.2012.02.040

10.1016/j.cell.2012.02.046

10.1016/j.neuron.2012.03.023

A Wimo, M Prince World Alzheimer Report 2010: The Global Economic Impact of Dementia (Alzheimer's Disease International, London), pp. 1–56 (2010).

10.1038/461895a

10.1038/nn.2583

10.1016/j.neuron.2011.01.002

10.1016/j.cell.2012.02.040

10.1016/j.expneurol.2009.07.035

10.1001/archneurol.2009.15

10.1212/01.wnl.0000171450.97464.49

10.1523/JNEUROSCI.4740-11.2011

10.1007/s12017-009-8109-7

10.1523/JNEUROSCI.2250-06.2006

10.1016/j.neuron.2007.07.025

10.1523/JNEUROSCI.5215-08.2009

10.1016/j.neurobiolaging.2009.09.002

10.1523/JNEUROSCI.4152-10.2011

10.1016/j.neuron.2010.10.020

10.1016/j.cell.2012.02.046

10.1038/nrd2997

10.1111/j.1527-3458.2007.00005.x

10.1111/j.1527-3458.2007.00004.x

10.1523/JNEUROSCI.2980-05.2005

10.1126/science.1141736

10.1074/jbc.M701078200

10.1523/JNEUROSCI.5341-09.2010

10.1016/S1474-4422(03)00584-2

10.1002/ana.21896

10.1038/nature09635

10.1073/pnas.1133381100

10.1038/nature05289

10.1016/S0896-6273(03)00124-7

10.1016/j.neuron.2005.10.028

10.1016/j.neuron.2008.02.003

10.1038/nn.2801

10.1111/j.1499-1654.2000.001499.x

10.1046/j.1528-1157.2002.18101.x

10.1111/j.1528-1167.2007.01516.x

10.1111/j.1528-1167.2006.00607.x

10.1016/S0920-1211(02)00247-4

10.1038/npp.2009.207

10.1016/j.neuropharm.2004.07.036

10.1038/nm.2127

10.1523/JNEUROSCI.0203-11.2011

10.1016/j.eplepsyres.2011.01.003

10.1016/S0140-6736(00)03600-X

10.2165/00002512-200320110-00001

10.1016/j.yebeh.2010.01.015

10.1073/pnas.0308208101

10.1523/JNEUROSCI.2699-05.2006

10.1523/JNEUROSCI.4521-08.2009

10.1016/j.seizure.2009.07.004

10.1152/jn.00279.2011

10.1016/j.brainres.2007.03.021

10.1016/j.neuron.2009.05.012

10.1038/nn.2433

10.1016/j.neurobiolaging.2008.08.009

10.1097/00001756-200303030-00035

KA Lyseng-Williamson, Levetiracetam: A review of its use in epilepsy. Drugs 71, 489–514 (2011).

10.1016/j.ceca.2009.12.014

10.1016/j.molmed.2009.01.001

10.1016/j.neuron.2009.07.003

10.1093/brain/122.9.1679

10.1016/j.neuroimage.2005.11.008

10.1111/j.1528-1167.2006.00427.x

10.1016/j.neuron.2012.03.023

10.1074/jbc.270.47.28257

10.1523/JNEUROSCI.20-11-04050.2000

10.1007/978-1-60761-744-0_17

10.1073/pnas.94.4.1550

10.1523/JNEUROSCI.23-26-08844.2003

10.1523/JNEUROSCI.0607-11.2011