Early Hippocampal Sharp-Wave Ripple Deficits Predict Later Learning and Memory Impairments in an Alzheimer’s Disease Mouse Model

摘要

Alzheimer’s disease (AD) is characterized by progressivememory loss, and there is a pressing needto identify early pathophysiological alterations thatpredict subsequent memory impairment. Hippocampalsharp-wave ripples (SWRs)—electrophysiologicalsignatures of memory reactivation in thehippocampus—are a compelling candidate for thispurpose. Mouse models of AD show reductions inboth SWR abundance and associated slow gamma(SG) power during aging, but these alterations haveyet to be directly linked to memory impairments. Inaged apolipoprotein E4 knockin (apoE4-KI) mice—amodel of the major genetic risk factor for AD—wefind that reduced SWR abundance and associatedCA3 SG power predicted spatial memory impairmentsmeasured 1–2 months later. Importantly,SWR-associated CA3 SG power reduction in youngapoE4-KI mice also predicted spatial memory deficitsmeasured 10 months later. These results establishfeatures of SWRs as potential functional biomarkersof memory impairment in AD.