Impaired Hippocampal Reactivation Preceding Robust Aβ Deposition in a Model of Alzheimer’s Disease

Current therapeutic strategies for Alzheimer’s disease (AD) target amyloid-beta (Aβ) fibrils and high molecular weight protofibrils associated with plaques, but other bioactive species may directly contribute to neural systems failure in AD. Employing hippocampal electrophysiological recordings and dynamic calcium imaging across the sleep-wake cycle in young mice expressing human Aβ and Aβ oligomers, we reveal marked impairments of hippocampal function long before amyloid plaques predominate. In slow wave sleep (SWS), Aβ increased the proportion of hypoactive cells and reduced place-cell reactivation. During awake behavior, Aβ impaired theta-gamma phase-amplitude coupling (PAC) and drove excessive synchronization of place cell calcium fluctuations with hippocampal theta. Remarkably, the on-line impairment of hippocampal theta-gamma PAC correlated with the SWS impairment of place-cell reactivation. Together, these results identify toxic effects of Aβ on memory encoding and consolidation processes before robust plaque deposition and support targeting soluble Aβ-related species to treat and prevent AD.