# Cognitive decline in aging and AD: neuroprotection by hypermyelination in FusOLcKO

> **NIH NIH R03** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $154,146

## Abstract

This R03 application aims to greatly improve understanding of oligodendrocytes and myelin support in
maintaining axonal integrity, synapse and neural network function in aging and Alzheimer’s disease (AD)/AD
Related Dementias (RD). Several lines of evidence support the early role of white matter and OL loss in AD.
Imaging studies in humans show white matter changes in AD before overt cognitive decline and RNA Seq studies
demonstrated that OLs are perhaps the most substantially impacted cell-type especially early in the course of
AD. Harnessing the neuroprotective effects of OL and myelin in AD/ADRD represents a novel strategy to halt
neurodegeneration early in the course of AD/ADRD. We plan to leverage our novel hypermyelinating FusOLcKO
mice that show enhanced motor and exploratory behavior. Early studies suggest that cortical neurodegeneration
is reduced and neuronal activity is enhanced in memory encoding regions of the FusOLcKO following brain
computer interface (BCI) probe implantation in young adult FusOLcKO mice. Lifelong myelination in the adult
brain supports neuronal networks plasticity underlying learning and maintenance of cognitive health. With aging
the efficiency of adult myelination weakens leading to memory decline and in AD it fails faster and early in the
course of the disease.
 This proposal aims to investigate if FUS dependent hypermyelination protects against neurodegeneration,
enhances neuronal activity and improves memory in aging and AD/ADRD by maintaining neural network
function. We will use quantitative structural and cellular analyses to assess neuroprotection and dynamic in vivo
electrophysiology recording to assess neural network activity. We will use standardized spatial memory testing
and metrics of adaptive myelination to measure the effect of hypermyelination on memory encoding and
consolidation in aged FusOL cKO mice. Finally, we will generate a new mouse line to study the neuroprotective
effect of hypermyelination in AD by crossing the FusOLcKO with the
humanized APP, AppNG-G-F line and perform
initial phenotypic and histological characterization studies. This new line represents a resource for future studies
and will be made available to the AD scientific community.
At completion of these studies, we expect to have
elucidated the protective effect of OL and myelin in cognitive strength in aging and to have generated a novel
AD hypermyelinating mouse model to serve as a resource for future studies on the role of myelin and OL in AD.

## Key facts

- **NIH application ID:** 10369130
- **Project number:** 1R03AG072218-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** FRANCA CAMBI
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $154,146
- **Award type:** 1
- **Project period:** 2022-01-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10369130

## Citation

> US National Institutes of Health, RePORTER application 10369130, Cognitive decline in aging and AD: neuroprotection by hypermyelination in FusOLcKO (1R03AG072218-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10369130. Licensed CC0.

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