# The Role of Peripheral Aged CD8+ T Cells in Hippocampal-Dependent Cognitive Decline

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $44,892

## Abstract

Project Summary
Aging is associated with age-related impairments in cognitive function and is the number one risk factor for a
series of neurodegenerative disorders, including Alzheimer’s disease. However, aging is not isolated to the brain,
but is instead a system wide process affecting multiple tissues and organ systems. A growing body of work has
demonstrated that exposure to an aged circulatory system, which connects all organ systems that face age-
related decline, drives hippocampal-dependent cognitive impairments during aging. Interestingly, there are
known age-related changes in the peripheral immune system, which constitutes an integral portion of the aging
circulatory system. T cells, a component of the adaptive immune system, are one of the immune cells most
detrimentally affected by age. In addition to a decrease in the ability to respond to infections and increases in
inflammatory cytokine secretion in the periphery, there is an emerging role posited for T cells in age-related brain
dysfunction. While studies have identified an increase in T cell infiltration into select areas of the aged brain, the
effect of age-related changes in circulating T cells on hippocampal-dependent cognitive function has not fully
been explored. Therefore, I sought to delineate the role of peripheral, aged CD8+ T cells in driving age-related
cognitive decline. Using single cell RNA sequencing, I identified age-associated CD8+ T cells, marked by
elevated expression of Granzyme K (GZMK), in spleens of cognitively impaired aged mice and young mice
exposed to an old circulatory system via heterochronic parabiosis. Interestingly, levels of secreted GZMK are
increased in the plasma of aged mice. Functionally, adoptive transfer of aged CD8+ T cells into young mice
resulted in cognitive deficits in hippocampal-dependent learning and memory, underlain by synaptic and
neuronal changes. To explore the rejuvenating potential of targeting aged CD8+ T cells, I selectively depleted
circulating CD8+ T cells in aged mice and observed amelioration of age-related impairments in learning and
memory. Interestingly, bulk RNA sequencing identified differentially expressed genes enriched in neurons and
endothelial cells. Consequently, this study aims to test the hypothesis that peripheral, age-associated CD8+ T
cells are drivers of cognitive impairments in the aging hippocampus. In Aim 1, I will determine the molecular and
cellular changes elicited by aged CD8+ T cells in the aged hippocampus. As depletion of circulating CD8+ T cells
is sufficient to ameliorate cognitive decline, in Aim 2, I will investigate the role of CD8+ T cell-derived factors in
promoting hippocampal-dependent cognitive decline, focusing on the pro-aging effects of GZMK. This study
aims to identify molecular mechanism by which circulating aged CD8+ T cells drive cognitive impairments with
age and identify potential therapeutic targets to counter aging-associated cognitive decline and dementia-related
neurode...

## Key facts

- **NIH application ID:** 10825980
- **Project number:** 1F31AG086042-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Juliana Sucharov Costa
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $44,892
- **Award type:** 1
- **Project period:** 2024-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10825980

## Citation

> US National Institutes of Health, RePORTER application 10825980, The Role of Peripheral Aged CD8+ T Cells in Hippocampal-Dependent Cognitive Decline (1F31AG086042-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10825980. Licensed CC0.

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