Hippocampal proteomics defines pathways associated with memory decline and resilience in normal aging and Alzheimer’s disease mouse models

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.

Aging‐associated changes in hippocampal glycogen metabolism in mice. Evidence for and against astrocyte‐to‐neuron lactate shuttle

“…This makes these analyses partial and not really quantitative in terms used by biology and chemistry (for review see Gizak & Rakus, ). The newest, gel‐free, studies of hippocampal proteome have been dedicated to investigate Alzheimer's disease‐related changes and do not provide information about energy metabolism changes during aging (e.g., Neuner, Wilmott, Hoffmann, Mozhui, and Kaczorowski, ). In contrast, the deepest gel‐free proteomic analysis of brain aging described by Walther and Mann () has been performed using adult and very old mice, respectively, 5 and 26 months‐old.…”

Postsynaptic Proteome of Non-Demented Individuals with Alzheimer’s Disease Neuropathology

“…Notably, keratin 9 was identified by multiple research groups in the cerebrospinal fluid and has been even proposed as a biomarker for AD [151–153]. Furthermore, keratin 1 was identified in 5xFAD mouse hippocampi using proteomics [154], and keratin 1 and 9 show different expression patterns in other neurodegenerative disorders [155]. …”

Emerging pathways driving early synaptic pathology in Alzheimer's disease

“…TRPC3, TRPC4 and TRPC5 may also contribute to SOCE alone or in heteromeric complexes with TRPC1, however TRPCs also have the potential to respond more directly to GPCR/diacylglycerol signaling, Ca 2+ and redox signals [109] and may be a preferred Ca 2+ channel target [29]. TRPC3 channels have been implicated as a Ca 2+ source limiting pyramidal neuron firing by activation of the medium and slow AHPs, and the expression of TRPC3 across 23 strains of mice was found to be negatively correlated with learning in the conditioned fear task [103]. Successful learning of the task was associated with down-regulation of TRPC3 and knockdown of TRPC3 improved memory performance.…”