title: Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model.
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.
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
authors.forename: Pascal E
authors.initials: PE
authors.lastname: Sanchez
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.forename: Laure
authors.initials: L
authors.lastname: Verret
authors.forename: Keith A
authors.initials: KA
authors.lastname: Vossel
authors.forename: Anna G
authors.initials: AG
authors.lastname: Orr
authors.forename: John R
authors.initials: JR
authors.lastname: Cirrito
authors.forename: Nino
authors.initials: N
authors.lastname: Devidze
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Ho
authors.forename: Gui-Qiu
authors.initials: GQ
authors.lastname: Yu
authors.forename: Jorge J
authors.initials: JJ
authors.lastname: Palop
authors.forename: Lennart
authors.initials: L
authors.lastname: Mucke
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology; D004569:Electroencephalography; D006801:Humans; D007150:Immunohistochemistry; D000077287:Levetiracetam; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009415:Nerve Net / Q000187:drug effects* / Q000503:physiopathology; D010889:Piracetam / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D013569:Synapses / Q000187:drug effects*
chemical_list: D016564:Amyloid beta-Protein Precursor; D000927:Anticonvulsants; D000077287:Levetiracetam; D010889:Piracetam