# Chaperome networks in Alzheimer's disease

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $1,165,073

## Abstract

ABSTRACT
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.

## Key facts

- **NIH application ID:** 10769858
- **Project number:** 5R01AG067598-04
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** OTTAVIO ARANCIO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,165,073
- **Award type:** 5
- **Project period:** 2021-02-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10769858

## Citation

> US National Institutes of Health, RePORTER application 10769858, Chaperome networks in Alzheimer's disease (5R01AG067598-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10769858. Licensed CC0.

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