# Targeting REST in Alzheimer's Disease

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2021 · $916,686

## Abstract

Project Summary/ Abstract
Memory loss in Alzheimer's disease (AD) reflects a progressive failure of neural network function in the setting
of pathology and neuroinflammation. The overall goal of this proposal is to explore a novel paradigm for the
role of the REST transcription factor in the modulation of neural networks and microglial function in AD, and to
advance a new therapeutic approach. We discovered that the master developmental regulator REST/NRSF is
induced in the aging human brain and coordinates the expression of a gene network that protects aging
neurons from neurotoxic stress and hyperexcitation. REST is downregulated in AD, beginning at the stage of
mild cognitive impairment. Our preliminary studies in conditional REST-deficient mice indicate that REST
protects against amyloid and tau pathology, as well as cognitive decline in AD mouse models. To begin to
understand the role of REST in critical neural circuits, we will generate highly selective knockouts of REST in
layer II entorhinal cortical neurons, or in CA1 or CA3 hippocampal neurons, components of the entorhinal
cortex (EC)-hippocampal circuit that is affected early in AD. These novel REST knockout mice will be crossed
with established AD transgenic lines to explore effects on neural network excitation, synaptic plasticity,
memory and pathology. We will also extend recent preliminary studies showing that REST is lost in microglia in
AD, and that REST-deficient microglia are functionally impaired. To explore the role of REST in microglia, we
have generated a conditional microglial REST-knockout mouse line. This mouse model, together with primary
microglial cell cultures, will be used to investigate REST-regulated immune/inflammatory signaling pathways,
as well as effects on phagocytosis and Aβ clearance. RNA-seq and ChIP-seq analysis will be performed to
broadly define REST-regulated gene networks and signaling pathways that affect microglial function. A central
question is whether REST is a druggable target. We have identified novel REST-activating drugs that prevent
memory loss and pathology in AD mouse models. Drug activity is lost in REST-deficient mice, indicating
specificity for REST. Importantly, the prototype REST-activating drug does not show evidence of toxicity in
mice following chronic administration for more than two years. These novel agents not only provide proof-of-
principle for translation, but are also valuable tools for discovering underlying mechanisms of REST-mediated
neuroprotection. One such mechanism is the unfolded protein response, which may be modulated by REST
activation through target genes and signaling pathways that will be investigated. This multidisciplinary
approach may provide novel insights into neuroprotective mechanisms in aging and AD, with potentially
important therapeutic implications.

## Key facts

- **NIH application ID:** 10209714
- **Project number:** 1R01AG069042-01A1
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Bruce A YANKNER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $916,686
- **Award type:** 1
- **Project period:** 2021-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10209714

## Citation

> US National Institutes of Health, RePORTER application 10209714, Targeting REST in Alzheimer's Disease (1R01AG069042-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10209714. Licensed CC0.

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