# Elucidating Novel Regulators of Microglial Phagocytosis in Alzheimer’s Disease

> **NIH NIH F99** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $38,682

## Abstract

Project Summary
Over 6 million Americans aged 65 and above currently suffer from Alzheimer's Disease (AD). This substantial
prevalence among the elderly underscores aging as one of the most prominent risk factors contributing to the
onset of AD. Microglia are cells that facilitate the clearance of cellular debris including protein aggregates through
the process of phagocytosis. Notably, microglial phagocytic function is impaired in both aging and AD, however,
the molecular mechanism that drives this dysfunction is not well characterized. My F99 work will delineate how
the loss of the RNA-binding protein, Quaking (Qki), drives phagocytic dysfunction in AD. My K00 work will follow
a similar path by focusing on how the dysregulation of an important phagocytic lipid, Phosphatidylinositol-3-
phosphate (PI3P), can lead to impairment in microglial membrane dynamics in the context of AD.
My sponsor's (Dr. Jian Hu) previous work has established the foundation to support the novel hypothesis that
Qki promotes microglial phagocytosis to attenuate AD progression. For Aim 1 (F99), I will be utilizing the
conditional deletion of Qki in microglia in an AD mouse model to 1) Assess the impact of Qki loss on the
development of AD pathology. 2) Isolate primary microglia to directly test phagocytic activity. 3) Perform a rescue
experiment with the agonist treatment of the Qki downstream transcription factor PPARβ. Published work
indicating the downregulation of PI3P in AD and PI3P enrichment in the phagocytic cup along with data from Dr.
Hu's lab indicating that PI3P synthesis is indirectly regulated by Qki has established the framework for my K00
research. My K00 work (Aim 2), will address the role of PI3P in the regulation of phagocytic membrane dynamic
and eventual contribution to AD progression through 1) Validating the expression of the PI3P and its synthesizing
enzyme Vps34 on the phagosome. 2) Utilizing conditional deletion of the Vps34 in microglia within AD mouse
models to characterize the impact of PI3P loss on AD progression.
Overall, this work will directly contribute to the NIA's priority of understanding the molecular mechanisms that
contribute to AD which is one of the most prevalent age-related neurodegenerative diseases. To successfully
complete my proposed aims, I will receive thorough training guided by an expert mentoring team in microglia
culture, transcriptomic analysis, lipidomic analysis, and AD mouse pathology characterization. Together, this
training will provide me with a well-equipped platform to succeed as an aging researcher with the establishment
of an independent research laboratory focused on delineating microglial dysfunction in AD.

## Key facts

- **NIH application ID:** 10972755
- **Project number:** 1F99AG088439-01
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Takese Tasseen McKenzie
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $38,682
- **Award type:** 1
- **Project period:** 2024-12-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10972755

## Citation

> US National Institutes of Health, RePORTER application 10972755, Elucidating Novel Regulators of Microglial Phagocytosis in Alzheimer’s Disease (1F99AG088439-01). Retrieved via MORVS 2026-10-24 from https://api.morvs.ai/grant/nih/10972755. Licensed CC0.

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