# Differential clearance of pyroglutamate abeta through arachnoid and meningeal lymphatics in Alzheimer Disease

> **NIH NIH R01** · WRIGHT STATE UNIVERSITY · 2020 · $376,763

## Abstract

Alzheimer's disease is a condition in which brain clearance of toxic peptides such as amyloid beta (Aβ) is
impaired. Determining the mechanisms by which brain clearance becomes compromised will open up
therapeutic opportunities for attenuating or preventing Alzheimer's disease. The field has focused much of
its attention on vascular risk factors such as Aβ transport at the blood-brain barrier. Despite significant
progress, the overarching problem of impaired Aβ brain 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 along with arachnoid membranes it 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 anatomical
connections largely remained a "black box." Before the discovery of Aβ, researchers also found that ligation
of cervical lymphatics resulted in cognitive impairment. However, a direct link between lymphatic drainage
and dementia was never established. Correlative data now suggest that the meninges are involved in
maintenance of brain health by managing the removal of endogenous waste to the systemic circulation. Yet
there has been 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. Our hypothesis is that the meninges play a necessary and specific
role in clearing neurotoxic pyroglutamate-Aβ (pE3-Aβ) and other Aβ species from the brain. We propose
that pathological changes in lymphatic vessels and arachnoid membranes occur during aging, thereby
promoting initiation or progression of Alzheimer's disease. To test this hypothesis, we have adapted the
TgF344-AD rat model that carries key hallmarks of Alzheimer's disease. This was cross-bred with a rat
expressing a fluorescent marker protein, so that lymphatic vessels are visualized in exquisite detail. In
parallel, we are systematically examining human meninges in Alzheimer's disease. Aim #1 will examine
energy-dependent mechanisms underlying lymphatic clearance, to provide new potential targets for drug
therapy. Aim #2 will confirm anatomical correlates of the lymphatic system in aging and will modulate its
function to prove causality and plasticity of the meningeal system. Aim #3 will establish the relevance of
meningeal clearance of pE3-Aβ and Aβ to human Alzheimer's disease by creating a high resolution map of
the human meninges and using proteomics and biochemical analysis to model clearance pathways. These
studie...

## Key facts

- **NIH application ID:** 10000006
- **Project number:** 5R01AG064226-02
- **Recipient organization:** WRIGHT STATE UNIVERSITY
- **Principal Investigator:** Christopher G. Janson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,763
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000006

## Citation

> US National Institutes of Health, RePORTER application 10000006, Differential clearance of pyroglutamate abeta through arachnoid and meningeal lymphatics in Alzheimer Disease (5R01AG064226-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10000006. Licensed CC0.

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