The goal of the proposed project is to address how neuronal stress triggered by amyloid-beta and tau oligomeric species induces protein connectivity dysfunctions and alters protein-to-neuronal circuit-to-organ level function. Our focus in on synaptic dysfunction and cognitive deficits in Alzheimer's disease (AD). The hypothesis behind our investigation is that upon entry, the molecular stress triggered by amyloid-beta and tau oligomeric species induces a maladaptive rewiring in the connectivity, and in turn the function of large subsets of downstream neuronal proteins and their networks, through pathologic chaperome scaffolds termed epichaperomes. This hypothesis is supported by preliminary data obtained by the Chiosis lab showing that neuronal lineages are especially prone to form epichaperomes following stressors, and that most vulnerable to epichaperomes are protein pathways with key roles in synaptic plasticity. Additional preliminary experiments supporting feasibility of our experimental plan are provided by studies from the Arancio laboratory and others demonstrating that A? and tau oligomers alter synaptic connectivity leading to memory loss. Our preliminary observation that dismantling the pathologic epichaperome structures into normal, folding chaperones rebalances protein network connectivity and functionality to those seen in physiological conditions, are also in support of our scientific premise. To execute these studies, we use iPSC-derived cellular models and mouse models of AD and combine the synergistic expertise of Drs. Arancio (synaptic plasticity, biology of AD), Chiosis (chemical biology of pathologic protein networks, translational research), Fraser (mouse models of AD and AD biology), Zhou (iPSC models in disease) and Mertens (consultant on hiPSC and iN-based cellular models for synaptic function study in AD). We expect that our studies will deliver proteome-wide functional insights and comprehensive, mechanistic understanding into how A? and tau oligomers lead to synaptic failure and cognitive defects. In addition to providing new insights into AD biology, our studies have immediate translational applications. With an epichaperome therapeutic discovered by the Chiosis lab moving into Phase 2 clinical evaluation in AD, hypotheses tested within the present proposal may have immediate impact in human AD.
We expect the results of this work will inform on a mechanism for defective rewiring in brain connectivity, and dysfunction of large subsets of neuronal proteins and their networks, by the so-called epichaperome, a maladaptive regulator of proteostasis. These are hypothesis-driven and clinically relevant studies into Alzheimer's disease that also provide insights into new aspects of Alzheimer's disease biology.
