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 molecular cascades associated with AD may drive neural systems failure before Aβ plaque deposition in AD. Employing hippocampal electrophysiological recordings and dynamic calcium imaging across the sleep-wake cycle in the APP/PS1 mouse model of AD before Aβ plaques accumulated, we detected marked impairments of hippocampal systems function: In a spatial behavioral task, but not REM sleep, phase-amplitude coupling (PAC) of the hippocampal theta and gamma oscillations was impaired and place cell calcium fluctuations were hyper-synchronized with the theta oscillation. In subsequent slow wave sleep (SWS), place cell reactivation was reduced. These degraded neural functions underlying memory encoding and consolidation support targeting pathological processes of the pre-plaque phase of AD to treat and prevent hippocampal impairments.