# REST and Neural Network Dysfunction in Alzheimer's Disease

> **NIH NIH R56** · HARVARD MEDICAL SCHOOL · 2020 · $626,369

## Abstract

This RO1 grant proposal is in response to FOA: PAR-19-070, Notice NOT-AG-19-033 “Selective Cell
and Network Vulnerability in Aging and Alzheimer's Disease”. Memory loss in Alzheimer's disease (AD)
reflects a progressive failure of neural network function. The overall goal of this proposal is to explore a novel
paradigm for the role of neural networks and the REST transcription factor in brain aging and AD. We have
shown that REST is activated in the aging human brain but not in AD, where it fails beginning at the stage of
mild cognitive impairment. Furthermore, we have recently demonstrated that regulation of neural network
activity by REST is involved in a conserved mechanism of longevity and cognitive preservation. Our
preliminary studies indicate that REST loss-of- function gives rise to cognitive decline, and markedly augments
amyloid and tau pathology in several AD mouse models. It remains to be determined, however, whether REST
selectively affects critical neural circuits or acts more globally. We have generated brain conditional floxed
REST knockout mice, and now propose to generate REST knockout mice that selectively target entorhinal
cortical neurons, CA1 or CA3 hippocampal neurons, or inhibitory GABAergic interneurons. These novel
conditional REST knockout lines, together with two established AD transgenic lines, will be used to interrogate
the role of REST in the entorhinal (EC)-hippocampal circuit that plays an essential role in memory formation
and is central to the onset of AD. Specifically, selective effects of targeted REST deletion on neural network
excitation, synaptic plasticity, memory, amyloid deposition and the propagation of tau pathology will be
assessed. Our working hypothesis is that REST will play a central role in the regulation of EC-hippocampal
network homeostasis, and that a breakdown of network function is an early component of AD. To complement
these in vivo studies, we have established a cerebral organoid model of sporadic AD and APOE4 to interrogate
neural network function. Cerebral organoids derived from sporadic AD and APOE4 gene-edited iPS cells will
be examined for altered neural network activity and tau propagation, and the role of REST. Non-invasive
electrical stimulation will be explored in cerebral organoids as an intervention for ameliorating network
dysfunction. Finally, we will employ a powerful new platform for single cell RNA-seq and ATAC-seq in the
brain. This approach will be applied to mouse models and the human brain to discover gene networks that
protect against age- and AD-related memory loss. This multidisciplinary approach will involve collaborating
investigators with expertise ranging from genomic biology to electrophysiology and neuropathology, in a
coordinated effort to advance the understanding of selective neural network dysfunction in AD.

## Key facts

- **NIH application ID:** 10229122
- **Project number:** 1R56AG069042-01
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Bruce A YANKNER
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $626,369
- **Award type:** 1
- **Project period:** 2020-09-30 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10229122

## Citation

> US National Institutes of Health, RePORTER application 10229122, REST and Neural Network Dysfunction in Alzheimer's Disease (1R56AG069042-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10229122. Licensed CC0.

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