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

Emily A Jones,Anna K Gillespie,Yadong Huang,Seo Yeon Yoon,Loren M Frank

doi:10.2139/ssrn.3362352

Abstract

Alzheimer's disease (AD) is characterized by progressive memory loss, and there is a pressing need to identify early pathophysiological alterations that predict subsequent memory impairment. Hippocampal sharp-wave ripples (SWRs) – electrophysiological signatures of memory reactivation in the hippocampus – are a compelling candidate for doing so. Mouse models of AD show reductions in both SWR abundance and associated slow gamma (SG) power during aging, but these alterations have yet to be directly linked to memory impairments. In aged apolipoprotein E4 knock in (apoE4-KI) mice – a model of the major genetic risk factor for AD – we found that reduced SWR abundance and associated CA3 SG power predicted spatial memory impairments measured 1–2 months later. Importantly, SWR-associated CA3 SG power reduction in young apoE4-KI mice also predicted spatial memory deficits measured 10 months later. These results establish features of SWRs as potential functional biomarkers of memory impairment in AD.

Highlights

Alzheimer’s disease (AD) is a form of dementia characterized by progressive cognitive decline that affects 11% of the United States population over the age of 65 (Hebert et al, 2013)
We found that deficits in sharp-wave ripples (SWRs) abundance and associated slow gamma (SG) power in CA3 predicted spatial memory impairment on both tasks in aged apoE4-KI mice
We began with a cohort of animals where we searched for potential predictive relationships between SWR features and behavioral performance in older animals

Summary

Introduction

Alzheimer’s disease (AD) is a form of dementia characterized by progressive cognitive decline that affects 11% of the United States population over the age of 65 (Hebert et al, 2013). While there are known genetic and environmental risk factors for AD (Ballard et al, 2011), our ability to predict which individuals will develop the disease, when symptoms will arise, and how rapidly they will progress remains poor. There is a pressing need to identify early pathophysiological alterations that can distinguish later cognitive decline from healthy aging. Predictive alterations, we studied a mouse model of ε4 variant of the APOE gene, the most common genetic risk factor for AD (Huang and Mucke, 2012; Liu et al, 2013). APOE ε4 has an allelic frequency of 20%–25% yet is found in 65%–80% of AD patients (Farrer et al, 1997). Mice with human APOE ε4 knocked in at the mouse Apoe locus (apoE4-KI) recapitulate age-dependent and sex-dependent memory deficits as seen in humans (Andrews-Zwilling et al, 2010; Beydoun et al, 2012; Caselli et al, 2009; Farrer et al, 1997; Leung et al, 2012)

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