# Targeting TFEB To Microglia and Monocytes to Enhance Amyloid Degradation

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $460,661

## Abstract

PROJECT SUMMARY / ABSTRACT
 The pathogenesis of Alzheimer’s disease (AD), the most common cause of dementia, is characterized by
the accumulation of Aβ in the interstitial fluid (ISF) and its aggregation into soluble oligomers and insoluble
amyloid plaques. This triggers a cascade of events including the formation of neurofibrillary tangles, neuronal
dysfunction and degeneration, ultimately resulting in clinical dementia. In sporadic AD, age-dependent
compromise of lysosome function in various brain cell types has been implicated in impaired Aβ metabolism,
resulting in accelerated pathogenesis. Microglia, the primary immune cell in the brain phagocytose Aβ and
amyloid plaques; but are observed to be engorged with residual amyloid material, suggesting impairment of
lysosomal degradative capacity. Microglia are an isolated self-renewing population within the brain and
peripheral monocytes do not cross the blood brain barrier under normal physiological conditions. Whether
monocytes enter the AD brain is a current source of controversy. Our preliminary data with a fate-mapping
strategy demonstrate that peripheral monocytes home in to amyloid plaques in aged APP/PS1 mice, a model of
AD pathogenesis and take up amyloid material. Peripheral monocytes are more amenable to targeting via gene
therapy or pharmacologic approaches than resident microglia and thus offer an opportunity to stimulate
lysosomal function in cells that will target plaques within the brain parenchyma. We have demonstrated that
exogenous expression of transcription factor EB (TFEB), a master inducer of lysosomal degradative pathways,
stimulates lysosome biogenesis and function in astrocytes, to upregulate Aβ uptake via macropinocytosis and
accelerate its lysosomal degradation resulting in attenuated amyloid plaques. Whether targeting TFEB to
resident microglia or circulating monocytes facilitates amyloid phagocytosis and lysosomal degradation to
attenuate plaque pathogenesis and improve neuronal function, needs to be explored.
Hypothesis: Ontogeny-based targeting of exogenous TFEB to microglia and peripheral monocytes is sufficient
to stimulate amyloid uptake and degradation; and attenuate amyloid plaques and neuronal pathology in AD.
To test this hypothesis, we propose three specific aims: SA1: Determine if enhancing lysosomal function with
TFEB expression in microglia attenuates plaque pathogenesis in AD mouse models. SA2: Examine the role of
peripheral monocyte recruitment in amyloid plaque pathogenesis. SA3: Determine if enhancing TFEB expression
specifically in circulating monocytes affects monocyte recruitment and plaque pathogenesis in AD mouse
models.

## Key facts

- **NIH application ID:** 10191054
- **Project number:** 5R01NS094692-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Abhinav Diwan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $460,661
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10191054

## Citation

> US National Institutes of Health, RePORTER application 10191054, Targeting TFEB To Microglia and Monocytes to Enhance Amyloid Degradation (5R01NS094692-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10191054. Licensed CC0.

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