Comparative profiling of the synaptic proteome from Alzheimer’s disease patients with focus on the APOE genotype

Hesse, R.; Llavero Hurtado, M.; Jackson, R.; Eaton, S. L.; Hermann, A. G.; Colom Cadena, M.; King, D.; Rose, J.; Tulloch, J.; McKenzie, C.-A.; Smith, C.; Henstridge, C.; Lamont, D.; Wishart, T.; Spires-Jones, T.

doi:10.1101/631556

bioRxiv · 10.1101/631556

Comparative profiling of the synaptic proteome from Alzheimer’s disease patients with focus on the APOE genotype

Hesse, R.·Llavero Hurtado, M.·Jackson, R.·Eaton, S. L.·Hermann, A. G.·Colom Cadena, M.·King, D.·Rose, J.·Tulloch, J.·McKenzie, C.-A.·Smith, C.·Henstridge, C.·Lamont, D.·Wishart, T.·Spires-Jones, T.

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Abstract

Degeneration of synapses in Alzheimers disease (AD) strongly correlates with cognitive decline, and synaptic pathology contributes to disease pathophysiology. We recently discovered that the strongest genetic risk factor for sporadic AD, apolipoprotein E epsilon 4 (APOE4), exacerbates synapse loss and synaptic accumulation of oligomeric amyloid beta in human AD brain. To begin to understand the molecular cascades involved in synapse loss in AD and how this is mediated by APOE, and to generate a resource of knowledge of changes in the synaptic proteome in AD, we conducted a proteomic screen and systematic in-silico analysis of synaptoneurosome preparations from temporal and occipital cortices of human AD and control subjects with known APOE gene status. Our analysis identified over 5,500 proteins in human synaptoneurosomes and highlighted disease, brain region, and APOE-associated changes in multiple molecular pathways including a decreased abundance in AD of proteins important for synaptic and mitochondrial function and an increased abundance of proteins involved in neuroimmune interactions and intracellular signaling.\n\nHighlightsO_LIProteomic analysis of synapses isolated from Alzheimers disease and control subject brains identifies over 5,500 proteins in human synapses.\nC_LIO_LIIn silico analysis reveals region-specific decreases in proteins involved in synaptic and mitochondrial function and increases in proteins involved in neuroimmune signaling and intracellular signaling in AD.\nC_LIO_LIThe apolipoprotein E4 risk gene is associated with exacerbated changes in synaptic proteins in AD.\nC_LI

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Hesse, R., Llavero Hurtado, M., Jackson, R., Eaton, S. L., Hermann, A. G., Colom Cadena, M., King, D., Rose, J., Tulloch, J., McKenzie, C.-A., Smith, C., Henstridge, C., Lamont, D., Wishart, T., Spires-Jones, T.. 2019-05-08. Comparative profiling of the synaptic proteome from Alzheimer’s disease patients with focus on the APOE genotype. https://doi.org/10.1101/631556

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