# Elucidating circuit disruptions in Alzheimer's disease

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $577,793

## Abstract

Summary
Alzheimer’s disease (AD) is the major cause of dementia currently without an effective cure. A number of
clinical trial failures has been reported due to a lack of complete understanding of Alzheimer’s disease etiology.
Neuronal activity disruptions have been described as contributing factors to the disease etiology and its
progression. Anomalies in slow wave activity, specifically slow oscillations (oscillations <1Hz) important for
consolidation of memories during NREM sleep, have been reported in Alzheimer’s patients and might have
contributed to their dementia. The cellular mechanisms of such disruptions however are unclear. Contributions
of neuronal hyperactivity have been suggested. It is unknown whether macroglia contribute to hyperactivity and
slow wave aberrations. Thus, there is an urgent need to understand the impact of macroglia on neuronal
activity disruptions, such as slow waves, to better understand AD etiology and to alleviate its dementia burden.
We will use transgenic mouse models of Alzheimer’s disease to systematically assess whether macroglia
contributes to neuronal activity disruptions using calcium imaging with multiphoton microscopy. We will also
investigate whether macroglia play a causal role in disruption of slow wave activity using optogenetics. We
hypothesize that macroglia play a role greater than that of a homeostatic regulator of neuronal activity. We
propose to employ optogenetics to control neuronal circuits aimed to restore neuronal activity and slow
Alzheimer’s disease progression. Thus, our findings will determine the cellular and molecular relationships
between neuronal activity and AD, with the targeting of macroglia as a novel therapeutic approach.

## Key facts

- **NIH application ID:** 10435537
- **Project number:** 5R01AG066171-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Ksenia V. Kastanenka
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $577,793
- **Award type:** 5
- **Project period:** 2020-09-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10435537

## Citation

> US National Institutes of Health, RePORTER application 10435537, Elucidating circuit disruptions in Alzheimer's disease (5R01AG066171-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10435537. Licensed CC0.

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