LAUSR

GRAPHICAL ABSTRACT Figure. No caption available. HIGHLIGHTSProteomics detects 36 hippocampal proteins associated with AD and normal aging memory deficits.Pathway analysis highlights HDAC4 as global regulator of memory deficits.103 proteins differ specifically in AD mice with intact vs impaired memory.Pathway analysis indicates disease‐specific involvement of REST and Gi signaling.Publically available proteomics resource for hypothesis generation and testing. 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 Gi 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.