# Chimeric Antigen Receptor Myeloid Cells for Alzheimer's Disease Therapy

> **NIH NIH F30** · WASHINGTON UNIVERSITY · 2024 · $34,623

## Abstract

PROJECT SUMMARY/ABSTRACT
The precise pathophysiology of Alzheimer’s disease (AD) remains unknown, but the development of amyloid-
beta (Aβ) plaques is thought to be a key initiating event preceding the formation of neurofibrillary tangles and
clinical disease. Anti-Aβ monoclonal antibodies (mAb) are the first disease modifying therapies approved for AD,
but clinical trials showed significant and potentially fatal dose-limiting side effects, including amyloid-related
imaging abnormalities (ARIA) that can manifest as edema and microhemorrhage. Peripheral
monocytes/macrophages enter the brain and associate with Aβ plaques in the APP/PS1 transgenic mouse model
of AD. These cells can reduce plaque load in vivo despite making up a small percentage of plaque-associated
macrophages, suggesting that a better mechanistic understanding of the recruitment and function of these cells
in the AD brain may improve anti-Aβ therapies. In preliminary work, a chimeric antigen receptor (CAR) was
expressed in macrophages (CAR-Ms) containing an extracellular Aβ binding domain and an intracellular Fc
receptor signaling domain to enhance the ability of these cells to phagocytose Aβ. Aβ CAR-Ms reduced plaque
load ex vivo on amyloid-laden APP/PS1 brain slices, and in vivo when injected into the hippocampus of APP/PS1
mice; however, plaque reduction was confined to the region immediately surrounding the cell injection site and
CAR-M migration was minimal, limiting its efficacy. The objective of this proposal is to enhance the efficacy of
Aβ CAR-Ms by identifying factors that promote the infiltration of peripheral monocytes into the brain and their
migration within the brain parenchyma. This proposal will test the hypothesis that improving brain infiltration and
migration of Aβ CAR-Ms will improve Aβ clearance in aged APP/PS1 mice without increasing ARIA. An important
theoretical advantage of CAR-M therapy compared to mAb therapy is the active degradation of plaque material,
potentially mitigating concerns for ARIA. Aim 1 will determine whether CX3CR1 overexpression allows CAR-Ms
to better infiltrate the brain from the periphery and characterize brain-penetrating CAR-Ms. This aim will further
investigate the effect of Aβ CAR-Ms on the composition and phenotype of the brain cellular microenvironment.
Aim 2 will compare the safety and efficacy of CAR-M therapy to mAb therapy in APP/PS1 mice. While mouse
models do not replicate the entire spectrum of human ARIA, the frequency of microhemorrhages after CAR-M
or mAb treatment will be quantified as a measure of ARIA-like phenomena. These studies will further develop
and characterize a novel form of AD therapy and provide insights in basic macrophage biology. I will pursue
these studies under the guidance of a team of physician-scientists, including a sponsor with expertise in CAR
and macrophage biology, and a co-sponsor with over two decades of experience in AD mouse modeling. My
training plan incorporates inter-departmental exper...

## Key facts

- **NIH application ID:** 10996769
- **Project number:** 1F30AG085987-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Alexander Kim
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $34,623
- **Award type:** 1
- **Project period:** 2024-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996769

## Citation

> US National Institutes of Health, RePORTER application 10996769, Chimeric Antigen Receptor Myeloid Cells for Alzheimer's Disease Therapy (1F30AG085987-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10996769. Licensed CC0.

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