# Aging dependent transformation of oligodendrocyte precursor cells

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $376,090

## Abstract

ABSTRACT
This application is submitted in response to the Notice of Special Interest (NOT-AG-21-018) for Alzheimer's-
focused administrative supplements for NIH grants. Our currently funded parent R01 titled “Aging dependent
transformation of oligodendrocyte precursor cells” does not currently focus on Alzheimer's disease (AD) or any
of its related dementias. In this supplement, we propose to leverage new technologies developed in our lab to
isolate at high purity and transcriptionally profile oligodendrocyte precursor cells (OPCs) from the murine brain,
regenerate OPCs in the adult CNS, and visualize the in vivo patterns of activity of OPCs in the intact CNS, to
explore how expression of human mutations linked to Alzheimer's disease (AD) alters the properties of these
ubiquitous progenitors. We will also explore whether “rejuvenation” of the OPC population through selective
genetic ablation and regeneration, alters the course of AD pathology. In Supplement Aim 1, we will use our
newly developed mouse line (Matn4-mEGFP) to isolate OPCs from mice that also express the 5xFAD
mutations and perform single cell RNA sequencing (scRNA-seq) at two different ages to determine how the
transcriptional landscape of OPCs is altered by the expression of these mutations and their emerging
pathological environment. These data will be computationally compared to our extensive OPC transcriptional
profiles at comparable ages from naïve mice. In Supplemental Aim 2, we will determine if ablation and
subsequent proliferative, homeostatic replacement of OPCs reduces the density of Aβ plaques in mice that
carry 5xFAD mutations. We will also assess whether homeostasis of OPCs is impaired in these AD model
mice. In Supplemental Aim 3, we will use longitudinal in vivo two photon imaging of OPCs in the visual cortex
to determine if spontaneous and neuron-evoked Ca2+ changes in OPCs are influenced by emerging pathology,
by simultaneously visualizing both OPC activity and Aβ plaque formation over weeks to months. These studies
will provide the first in vivo analysis of OPC Ca2+ activity in the context of CNS disease and may reveal new
pathways through which the dynamics of these cells are regulated. Together, these innovative studies will
provide new insight into how AD influences the behavior of OPCs, with relevance myelin homeostasis, Aβ
plaque formation and Aβ clearance. This knowledge may guide new approaches for manipulating the
properties of OPCs to achieve therapeutic benefit in slowing disease onset and reversing disease-associated
pathologies that induce cognitive decline and dementia.

## Key facts

- **NIH application ID:** 10498126
- **Project number:** 3R01AG072305-02S1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** DWIGHT E BERGLES
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $376,090
- **Award type:** 3
- **Project period:** 2021-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10498126

## Citation

> US National Institutes of Health, RePORTER application 10498126, Aging dependent transformation of oligodendrocyte precursor cells (3R01AG072305-02S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10498126. Licensed CC0.

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