Faculty Collaboration Database

Hippocampal proteomics defines pathways associated with memory decline and resilience in normal aging and Alzheimer's disease mouse models. Behav Brain Res 2017 Mar 30;322(Pt B):288-298

Date

06/07/2016

Pubmed ID

27265785

Pubmed Central ID

PMC5135662

DOI

10.1016/j.bbr.2016.06.002

Scopus ID

2-s2.0-84995700490 (requires institutional sign-in at Scopus site)   77 Citations

Abstract

Alzheimer's disease (AD), the most common form of dementia in the elderly, has no cure. Thus, the identification of key molecular mediators of cognitive decline in AD remains a top priority. As aging is the most significant risk factor for AD, the goal of this study was to identify altered proteins and pathways associated with the development of normal aging and AD memory deficits, and identify unique proteins and pathways that may contribute to AD-specific symptoms. We used contextual fear conditioning to diagnose 8-month-old 5XFAD and non-transgenic (Ntg) mice as having either intact or impaired memory, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify hippocampal membrane proteins across groups. Subsequent analysis detected 113 proteins differentially expressed relative to memory status (intact vs impaired) in Ntg mice and 103 proteins in 5XFAD mice. Thirty-six proteins, including several involved in neuronal excitability and synaptic plasticity (e.g., GRIA1, GRM3, and SYN1), were altered in both normal aging and AD. Pathway analysis highlighted HDAC4 as a regulator of observed protein changes in both genotypes and identified the REST epigenetic regulatory pathway and G_i intracellular signaling as AD-specific pathways involved in regulating the onset of memory deficits. Comparing the hippocampal membrane proteome of Ntg versus AD, regardless of cognitive status, identified 138 differentially expressed proteins, including confirmatory proteins APOE and CLU. Overall, we provide a novel list of putative targets and pathways with therapeutic potential, including a set of proteins associated with cognitive status in normal aging mice or gene mutations that cause AD.

Author List

Neuner SM, Wilmott LA, Hoffmann BR, Mozhui K, Kaczorowski CC

MESH terms used to index this publication - Major topics in bold

Aging
Alzheimer Disease
Amyloid beta-Protein Precursor
Animals
Chromatography, Liquid
Disease Models, Animal
Fear
Hippocampus
Humans
Memory
Memory Disorders
Mice, Transgenic
Presenilin-1
Proteome
Proteomics
Psychological Tests
Resilience, Psychological
Tandem Mass Spectrometry