Selective interactome vulnerability across the Alzheimer’s disease spectrum

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ABSTRACT Mechanisms underlying selective vulnerability from cells to networks across the Alzheimer's disease (AD) spectrum remain unknown, limiting our understanding of disease and hampering development of effective therapies. We propose to identify protein-protein interaction (PPI) network dysfunctions in brain cells and regions as a gateway to selective vulnerability mechanisms in AD. To gain systems level insights, we propose to leverage our discoveries in stress biology linking interactome network perturbations to the formation of long-lived oligomeric scaffolds termed epichaperomes, and to employ a novel `omics platform called epichaperomics that provides direct information on PPI network changes. Preliminary studies indicate epichaperomes change how thousands of proteins interact and negatively impact PPI networks important for neuronal function, including synaptic plasticity, cell-to-cell communication, protein translation, cell cycle re-entry, axon guidance, metabolic processes and inflammation, leading to cell and connectome-wide dysfunction and cognitive decline. Parallel studies in transgenic mice and iPSC-derived neurons demonstrate epichaperome formation is a key event that negatively impacts cellular function, from early prodromal disease stages and throughout disease progression. Preliminary results in transgenic mice and postmortem AD brains suggest epichaperome formation occurs principally within vulnerable brain cells and regions. Accordingly, we hypothesize epichaperome formation, and in turn of epichaperome-mediated PPI network imbalances, over decades, not only results in defects within intrinsic neuronal proteins and protein pathways but also intercellularly, where it disrupts intrinsic network connectivity of cells and of brain circuits. We posit vulnerable neurons and brain regions have a higher propensity to accumulate epichaperomes, and epichaperome-mediated dysfunctions. In accordance with NOT-AG-21-040, we propose to uncover mechanisms of PPI dysfunctions within individual brain cells and regions as a portal into selective vulnerability in AD, which remains unknown and a key missing piece. We aim to i) investigate mechanisms that enable (i.e., epichaperomes, Aim 1) and ii) those that execute (i.e., impacted proteins and protein pathways, Aim 2) context-specific dysfunctions in PPI networks. As a key element in linking stressors-to- phenotype, we aim to uncover cell- and region-specific vulnerabilities within PPI networks induced by individual stressors (Aim 3). Results provide first-of-a-kind insights into the spatio-temporal formation and distribution of epichaperomes across the AD spectrum and their relationship to clinical, pathologic, and genetic vulnerabilities. Outcomes are critical proteome-wide insights into interactome vulnerabilities, both on the nature and trajectory within vulnerable brain cells and brain regions. Raw datasets and data analytics will be deposited directly into free access sites for mining and hypothesis testing by members of the scientific community. In addition to defining technically challenging mechanistic insights into selective AD vulnerabilities, innovation includes diagnostics and therapeutics, as epichaperome-mediated dysfunctions are both imageable and targetable.