# Establishing the role of lymphatic clearance of amyloid beta in Alzheimer's disease

> **NIH NIH K01** · RUSH UNIVERSITY MEDICAL CENTER · 2021 · $124,850

## Abstract

Abstract
Alzheimer's disease is a condition in which brain clearance of toxic peptides such as amyloid beta (Aβ) is known to
be impaired. Determining the specific mechanisms by which brain clearance becomes impaired will open up
therapeutic opportunities for attenuating or preventing Alzheimer's disease. The field has focused considerable
attention on vascular risk factors such as Aβ transport at the blood-brain barrier, but this knowledge has not yet led
to breakthrough treatments. Despite some progress, the problem of impaired Aβ clearance has not been solved.
Thus, there is a need to consider alternative routes or mechanisms of clearance. The recently discovered meningeal
lymphatic system is a prime candidate for the missing link between impaired Aβ clearance and Alzheimer's disease.
This previously unrecognized network of intracranial drainage vessels is located in the meninges, or membranes
surrounding the brain, and actively participates in clearance of fluid and solutes from the brain. For many years, it
was known that substances injected into the brain make their way to the lymphatic drainage system in the head and
neck, but the anatomical connections largely remained a "black box." Before the discovery of Aβ, researchers also
found that ligation of cervical lymphatics resulted in cognitive impairment, but a direct link between lymphatic
drainage and dementia was never established. Correlative data now suggest that the meningeal lymphatic system is
involved in maintenance of brain health by managing the removal of endogenous waste to the systemic circulation.
Yet there is no clear functional link between meningeal lymphatics and major pathological features of Alzheimer's
disease, and it is furthermore unclear how lymphatic function would become compromised during disease initiation
or progression. My hypothesis is that pathological changes develop in the meningeal lymphatics during the aging
process, thereby promoting initiation or progression of Alzheimer's disease. To test this hypothesis, my lab has
adapted the best available rat model of Alzheimer's disease which carries all the hallmarks of the human disease.
This transgenic Alzheimer's disease rat was cross-bred with another rat expressing a fluorescent marker protein in
the lymphatic vasculature, so the full extent of vessels is visualized in exquisite detail. Using this hybrid triple
transgenic rat model, the hypothesis will be tested by first determining a direct causal relationship between failure of
the meningeal lymphatic system and the development of Alzheimer's disease. This will be accomplished in Specific
Aim #1 which will modulate its function using novel surgical approaches to impair the drainage exit routes of the
lymphatic vasculature. In order to define the precise anatomical localization of the meningeal lymphatic system in
Alzheimer's disease progression, which will enable drug development, Specific Aim #2 will determine the time
course and magnitude of structural c...

## Key facts

- **NIH application ID:** 10134185
- **Project number:** 5K01AG062789-03
- **Recipient organization:** RUSH UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** LIUDMILA G ROMANOVA
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $124,850
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134185

## Citation

> US National Institutes of Health, RePORTER application 10134185, Establishing the role of lymphatic clearance of amyloid beta in Alzheimer's disease (5K01AG062789-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10134185. Licensed CC0.

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