Selective interactome vulnerability across the Alzheimer’s disease spectrum

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ABSTRACT Our application proposes to identify interactome network vulnerabilities in brain regions and cell populations that are selectively dysregulated in Alzheimer's disease (AD). The goals are to discover across the AD spectrum the mechanisms underlying such selective vulnerability. To gain systems level insights into interactome dysfunctions, we propose to make use of our discoveries in stress biology linking interactome network perturbations to the formation of long-lived oligomeric scaffolds termed epichaperomes, and of a novel `omics platform called chaperomics that provides direct information on interactome network changes. Our preliminary studies show epichaperomes change how thousands of proteins interact and negatively impact interactome 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 network-wide dysfunction and cognitive decline. Studies in transgenic mice and iPSC-derived neurons position epichaperome formation as an event that negatively impacts cellular function, from early in the disease process and throughout disease progression. Studies in transgenic mice and AD patients suggest epichaperome formation within AD vulnerable brain regions. These studies enable us to hypothesize accumulation of epichaperomes, and in turn of epichaperome-mediated interactome 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 (e.g., hippocampus and regions of the default mode network) have a higher propensity to accumulate epichaperomes, and in turn epichaperome-mediated dysfunctions, due to their intrinsic anatomy and biochemistry. In line with PAR-19-070, we intend to test these hypotheses within clinically and neuropathologically well-characterized postmortem human brains. We aim to investigate the regional and temporal trajectory of epichaperome formation (Aim 1) and to determine the negative impact of epichaperome formation on brain regions selectively vulnerable in AD (Aim 2). We also plan to explore neural cell populations most affected by this newly recognized pathologic mechanism (Aim 3). Outcomes are first-of-a-kind insights into the spatio-temporal distribution of epichaperomes across the AD spectrum and their relationship to clinical, pathologic and genetic vulnerabilities. Outcomes are also proteome-wide insights into interactome networks' vulnerabilities and dysfunctions, both on their nature and trajectory in vulnerable brain regions. Raw datasets and data analytics from interactome network studies will be deposited into free-access portals for mining and hypothesis generating access by the scientific community. A web-based user-interface will be designed to facilitate data processing and visualization. In addition to defining technically challenging insights into interactome dysfunctions and vulnerabilities, innovation includes both diagnostics and therapeutics, as epichaperome-mediated vulnerabilities are both targetable and imageable.