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; Seo Yeon Yoon; Loren M Frank; Yadong Huang

doi:10.1016/j.celrep.2019.10.056

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

Cell Rep. 2019 Nov 19;29(8):2123-2133.e4. doi: 10.1016/j.celrep.2019.10.056.

Authors

Emily A Jones¹, Anna K Gillespie², Seo Yeon Yoon³, Loren M Frank², Yadong Huang⁴

Affiliations

¹ Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
² Kavli Institute for Fundamental Neuroscience and Department of Physiology, University of California, San Francisco, San Francisco, CA 94143, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
³ Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
⁴ Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Departments of Neurology and Pathology, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: [email protected].

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 this purpose. 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 knockin (apoE4-KI) mice-a model of the major genetic risk factor for AD-we find 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.

Keywords: Alzheimer’s disease; CA3; apolipoprotein E4; biomarker; hippocampus; learning; memory; sharp-wave ripple; slow gamma.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / metabolism*
Alzheimer Disease / pathology
Animals
Apolipoprotein E4 / metabolism
Biomarkers / metabolism
CA3 Region, Hippocampal / metabolism
CA3 Region, Hippocampal / pathology
Disease Models, Animal
Hippocampus / metabolism*
Hippocampus / pathology
Learning / physiology
Memory Disorders / metabolism*
Memory Disorders / pathology
Mice
Risk Factors
Spatial Memory / physiology

Substances

Apolipoprotein E4
Biomarkers

Abstract

Publication types

MeSH terms

Substances

Grants and funding