# Effect of Brain Lymphatic Activation on Alzheimer's Disease Progression

> **NIH NIH R21** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2022 · $453,750

## Abstract

PROJECT SUMMARY
Failure of brain waste clearance by the cerebrospinal fluid outflow has been associated with various neurological
diseases. Disruption of the meningeal lymphatics in Alzheimer's disease (AD) mouse models leads to amyloid-
β deposition in the meninges and aggravates parenchymal Aβ accumulation. The 5xFAD mouse model displays
impaired lymphatic function and contractility and significantly delayed brain fluid outflow. These results suggest
that meningeal lymphatics profoundly contribute to brain fluid homeostasis and that optimal brain fluid drainage
is critical for maintaining brain health and function. Consistently, our preliminary studies demonstrate that
activation of the brain lymphatics through a mechanosensor Piezo1 expedited the brain fluid outflow in two
mouse models with abnormal brain fluid accumulation. Together, we hypothesize that enhancing the brain
lymphatic drainage would offer therapeutic benefits to AD. To address this hypothesis, we propose to stimulate
the brain lymphatic drainage by genetic (Aim1) and chemical (Aim2) activations of Piezo1, followed by evaluating
their effects on the initiation and progression of AD. Together, the outcome of this work will not only identify
Piezo1 as a novel target for AD, but also provide a conceptual foundation for enhancing the brain lymphatic
drainage as a novel therapeutic approach against various neurological diseases.

## Key facts

- **NIH application ID:** 10540194
- **Project number:** 1R21AG076232-01A1
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Young-Kwon Hong
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $453,750
- **Award type:** 1
- **Project period:** 2022-08-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10540194

## Citation

> US National Institutes of Health, RePORTER application 10540194, Effect of Brain Lymphatic Activation on Alzheimer's Disease Progression (1R21AG076232-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10540194. Licensed CC0.

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