# Aged T-cell-derived cytokines impact meningeal lymphatics and contribute to AD

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $578,141

## Abstract

PROJECT SUMMARY
Many age-related neurodegenerative diseases—including Alzheimer's disease (AD)—are associated with
misfolded protein deposition that promote inflammatory responses, neuronal dysfunction, and cognitive deficits.
We have recently identified that aging and AD both display impaired meningeal lymphatic function, which
ultimately results in impaired CSF drainage to deep cervical lymph nodes, as well as CSF perfusion into the
brain parenchyma, collectively promoting waste build up and A-induced pathologies in AD mice. Our preliminary
data demonstrate that aging is also associated with the accumulation of IFNγ-producing CD4 and CD8 T cells
in the dural meninges, closely associated with the meningeal lymphatics. IFNγ signaling represents a
transcriptional hallmark of aged meningeal lymphatics and augmentation of this axis in young mice attenuates
their functional drainage of CSF. We therefore hypothesize that during aging and in AD, elevated expression of
IFNγ from meningeal CD4 and CD8 T cells impairs meningeal lymphatic function function via direct signaling on
their IFNγ receptors, leading to meningeal lymphatic deterioration. Such deterioration later results in impaired
brain perfusion by cerebrospinal fluid (CSF), subsequently leading to the accumulation of debris and worsening
progression of AD. We further hypothesize that using cytokine neutralizing antibodies, we can preserve
meningeal lymphatics in aged mice and prevent or reduce the age-associated brain dysfunctions and augment
existing immunotherapy strategies in AD patients. Addressing our hypotheses of this proposal will illuminate
mechanistic pathways underlying age-related meningeal lymphatic dysfunction, and identify new promising
avenues for therapeutic interventions intended to reduce AD-related pathology.

## Key facts

- **NIH application ID:** 10897002
- **Project number:** 5R01AG078667-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jonathan Kipnis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $578,141
- **Award type:** 5
- **Project period:** 2022-08-17 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10897002

## Citation

> US National Institutes of Health, RePORTER application 10897002, Aged T-cell-derived cytokines impact meningeal lymphatics and contribute to AD (5R01AG078667-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10897002. Licensed CC0.

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