# Overlapping Molecular Dysregulation of Endolysosomal Function in Alzheimer's Disease and FTLD-TDP

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $775,259

## Abstract

SUMMARY
Alzheimer’s Disease (AD) progresses slowly and involves many molecular pathways. In addition to accumulation
of Aß plaques and Tau neurofibrillary tangles, there are also inflammatory, vascular and metabolic changes.
Human genetic studies of late onset AD (LOAD) risk have identified two major groups of genes, one related to
brain inflammation and another with established roles in the endolysosomal pathway. Endolysosomal organelles
are utilized by cells to take up, degrade and remove substances from both inside and outside of the cell. The
general principles of endolysosomal regulation/dysregulation in AD are not well understood. However, an
endolysosomal pathway role is not specific to AD amongst degenerative dementias. In the related condition of
Fronto-Temporal Dementia, Progranulin and TMEM106B proteins play key roles, and are linked to the
endolysosomal pathway. Here, we seek to leverage knowledge of this FTLD-TDP pathway to understand and
modify endolysosomal function in AD and in Tauopathy.
Our studies of mice lacking Progranulin suggest that this endolysosomal protein has a pronounced effect on
Tau-dependent neuro-degeneration. In Preliminary studies, Tau transgene induced phenotypes are fully rescued
by loss of Progranulin. In proposed work, we will characterize this exciting finding with regard to the molecular
and cellular details of Tau aggregation, phosphorylation, spreading, metabolism and toxicity. These studies will
define a role of Progranulin-dependent regulation of endolysosomes in Tauopathies, including AD. Loss of a
second endolysosomal protein, TMEM106B, counteracts loss of Progranulin in certain settings, but not others.
For Tauopathy and AD, we will test whether reducing TMEM106B function worsens pathophysiology, and if
increasing TMEM106B mimics the loss of Progranulin to rescue Tauopathy. The long-term goal is to define a
neuro-degeneration-related endolysosomal pathway that can be targeted to provide disease-modifying therapy
for Tauopathies, including Alzheimer’s Disease.

## Key facts

- **NIH application ID:** 10221595
- **Project number:** 5R01AG066165-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** STEPHEN M STRITTMATTER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $775,259
- **Award type:** 5
- **Project period:** 2019-09-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10221595

## Citation

> US National Institutes of Health, RePORTER application 10221595, Overlapping Molecular Dysregulation of Endolysosomal Function in Alzheimer's Disease and FTLD-TDP (5R01AG066165-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10221595. Licensed CC0.

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