# Metabolic determinants of reactive astrogliosis and cognitive heterogeneity in aging

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2024 · $449,629

## Abstract

ABSTRACT
The greatest risk factor for Alzheimer’s disease and related dementias (ADRD) is aging, but the mechanisms that
link aging to ADRD disease processes are largely unknown. Of particular interest, recent single-cell transcriptomic
studies of aged hippocampal astrocytes, and multi-transcriptomic analysis of astrocytes from human AD samples
and a mouse model of AD, show commonalities in the decline of mitochondrial oxidative phosphorylation
(OXPHOS) and mitophagy related pathways. Although cognitive function can decline with age, many human and
animal model subjects retain function. Current behavioral/cognitive testing paradigms are inefficient at discerning
cognitive trajectories in aging. We have developed a unique automated home-cage testing paradigm for spatial
memory that can reliably stratify cognitive performance in aged mice into cognitively ‘intact’ and ‘impaired’
subgroups. Molecular analyses show significant declines in OXPHOS genes, mitochondrial function and
concomitant increases in markers of astrogliosis specifically in ‘impaired’ mice. Whether impairments in astrocyte
mitochondrial function are a driver of reactive astrogliosis associated with cognitive impairment in aging and AD
is unresolved and is a critical question since it guides future therapeutic interventions. Our central hypothesize
is that deficits in astrocyte mitochondrial function and mitochondrial proteostasis drive reactive
astrogliosis that contribute to cognitive impairment in aging and AD, and that therapies that improve
astrocyte mitochondrial function will delay cognitive decline. The following aims are proposed: Aim 1.
Identify astrocyte subtypes with dysfunctional mitochondria in hippocampus of cognitively impaired
aged mice. We will use high resolution respirometry to measure mitochondrial function in isolated hippocampal
mitochondria from aged cognitively stratified mice. We will perform scRNAseq on hippocampal astrocytes to
identify subtypes that are specific to cognitive impairment and allow us to differentiate between healthy aging
and cognitive impairment. Aim 2. Define the role of mitochondrial proteostasis in reactive astrogliosis of
aged mice. We will assess mitochondrial protein turnover rates as well as turnover of targeted mitochondrial
proteins using D2O labeling of proteins in astrocytes from young, aged-intact and -impaired mice and determine
the contribution of mitophagy to astrocyte-mediated cognitive decline in aging. We expect these experiments will
link decreased mitochondrial protein turnover rate and mitophagy to the genesis of reactive astrogliosis and
cognitive impairment. Aim 3. Determine whether interventions that improve astrocyte mitochondrial
function alleviate cognitive impairment in aged and APP/PS1 mice. We will use AAV5-mediated
overexpression of SOD2 specifically in astrocytes delivered via stereotactic injections into the hippocampus of
cognitively stratified aged, and APP/PSI mice. We expect that the intervention will ...

## Key facts

- **NIH application ID:** 10806840
- **Project number:** 1R01AG085398-01
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Sreemathi Logan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $449,629
- **Award type:** 1
- **Project period:** 2024-09-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10806840

## Citation

> US National Institutes of Health, RePORTER application 10806840, Metabolic determinants of reactive astrogliosis and cognitive heterogeneity in aging (1R01AG085398-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10806840. Licensed CC0.

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