# Mapping and modeling inhibitory interneurons in Alzheimer's disease and related dementias: novel strategies to reverse neural network dysfunction

> **NIH NIH K08** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $169,560

## Abstract

ABSTRACT
Alzheimer’s disease (AD) and AD-related dementias (ADRD) are prevalent and costly, with no
disease-modifying therapies. Emerging data demonstrate that disruptions within inhibitory
interneurons contribute significantly to AD/ADRD pathophysiology. Interneurons normally
regulate excitatory firing of neuronal networks, enabling the tuning and adaptability of circuits
which subserve functions such as memory and cognition. Altered interneuron inhibition is seen
in brains of human AD/ADRD subjects, which leads to hyperexcitability, hypersynchrony, and
epileptiform activity that impairs memory and cognition. Synaptic overactivity also increases
amyloid beta (Aβ) levels, while enhancing interneuron inhibitory activity promotes Aβ clearance.
Yet, the upstream causes of interneuron dysfunction in AD/ADRD are unclear. There is a critical
need to define mechanisms of interneuron pathology and the resultant hyperexcitability in
AD/ADRD to develop effective therapies. This proposal will catalog mediators of interneuron
dysfunction, and develop strategies to reverse this pathology. Our central hypothesis is that
abnormal mitochondrial function is a major and early contributor to interneuron dysfunction, and
that transplantation of iPSC-derived interneuron precursors will restore cognitive and memory
circuits. Our rationale is that, by defining faulty interneuron biology and connections, concrete
therapeutic targets will be made feasible for AD/ADRD. We have three Aims. Aim 1 will identify
disrupted interneuron gene expression by studying interneurons within hippocampal and cortical
subregions of human post-mortem AD brain. Using a spatial transcriptomic whole transcriptome
approach, we will map aberrant interneuron genes and identify mechanistic targets for reversing
hyperexcitability and restoring cognitive function. Aim 2 will define inhibitory dysfunction in vitro
by characterizing AD-derived induced interneurons using metabolic phenotyping,
immunocytochemical staining, and Aβ toxicity assays. AD-derived interneurons will then be
modified to express genes aimed at reversing abnormalities seen in prior studies with the goal
of restoring interneuron regulatory physiology. This aim will determine whether corrected
interneurons represent a viable patient-specific therapeutic strategy. Aim 3 will transplant
healthy induced interneurons into hippocampal structures of an AD mouse model, assessing
graft survival and hippocampal-based memory performance. Here, we will determine the impact
of interneuron augmentation on behavior and neurodegeneration in vivo, providing a rationale
for future cell-based therapies. Overall, understanding interneuron pathophysiology and its
contribution to neural circuit dysregulation in AD/ADRD will help uncover innovative treatments
for AD/ADRD and similar illnesses involving dysregulated neural networks.

## Key facts

- **NIH application ID:** 10982669
- **Project number:** 1K08AG084902-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Kevin Showen Chen
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $169,560
- **Award type:** 1
- **Project period:** 2024-08-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10982669

## Citation

> US National Institutes of Health, RePORTER application 10982669, Mapping and modeling inhibitory interneurons in Alzheimer's disease and related dementias: novel strategies to reverse neural network dysfunction (1K08AG084902-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10982669. Licensed CC0.

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