Hippocampal proteomics defines pathways associated with memory decline and resilience in normal aging and Alzheimer's disease mouse models.
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 Giintracellular 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.
Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, United States.
Sarah M
SM
Neuner
Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, United States.
Lynda A
LA
Wilmott
Department of Medicine, Division of Cardiology and Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, WI, 53226 United States.
Brian R
BR
Hoffmann
Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, United States.
Khyobeni
K
Mozhui
Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, United States. Electronic address: ckaczoro@uthsc.edu.
Catherine C
CC
Kaczorowski
D000375:Aging / Q000378:metabolism* / Q000523:psychology*; D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002853:Chromatography, Liquid; D003213:Conditioning, Psychological; D004195:Disease Models, Animal; D005239:Fear; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008568:Memory / Q000502:physiology; D008569:Memory Disorders / Q000378:metabolism*; D008822:Mice, Transgenic; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D020543:Proteome; D040901:Proteomics; D011581:Psychological Tests; D055500:Resilience, Psychological; D053719:Tandem Mass Spectrometry
C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D053764:Presenilin-1; D020543:Proteome
Aging; Alzheimer’s disease; Cognition; Ion channels; Proteomics