# Amyloid Beta CAR Macrophages: a cell engineering strategy to clear pathogenic proteins

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $715,640

## Abstract

Phagocytosis by microglia, the brain's resident macrophages, is central to Alzheimer Disease (AD) risk and
pathogenesis. Current β-amyloid (Aβ) clearing immunotherapies use monoclonal antibodies to indirectly elicit
phagocytosis, in an attempt to reverse AD manifestations. This form of passive immunization induces microglial
reactivity and neuroinflammation, two features abundant in AD neuropathologic specimens. Due to a dearth of
tools, prior mechanistic study of microglia-Aβ interactions used loss of function strategies such as Trem2 KO or
microglial depletion, leaving uncertain whether microglial Aβ phagocytosis itself is sufficient to alter
neuropathology. To address this knowledge gap, we
clearance
engraftment
test
engineered macrophages to achieve specific amyloid
with antigen receptors ( AβCAR) , and developed methods for efficient macrophage
in the brain. This dual PI proposal unites experts in immune cell therapies and microglial biology to
the overarching hypothesis that
Aβ-chimeric
AβCAR-engineered macrophages effectively clear amyloid in vivo
and that associated neuroinflammation is prevented by manipulation of the inflammasome. In
preliminary data we successfully engineered AβCAR
engulf
into
determine
engraft
neuropathology
and
AβCAR
exposure
NLRP3
on
transplant
determine
in
Aim
inflammasome
close
to
 expressing macrophages, found that they specifically
amyloid chemotherapy-dependent and - independent methods to transplant macrophages
 the mouse brain at unprecedented efficiency, ensuring the feasibility of this proposal. In Aim 1 we will
 how active cell-based Aβ targeting affects amyloid pathology in murine models. To do so, we will
 AβCAR macrophages into the 5xFAD model of Aβ pathology and measure their effects on
and behavior. Aim 1 will clarify the controversial relationship between microglial Aβ phagocytosis
pathology using a cell engineering strategy with high t herapeutic potential. Where Aim 1 focuses on how
macrophages affect the brain Aβ, Aim 2 addresses how brain Aβ in turn affects macrophages. Amyloid
 induces microglial state changes and neuroinflammation, with strong mechanistic data implicating
inflammasome signaling as a major driver. Aim 2 will therefore elucidate the effects of AβCAR targeting
microglial reactivity, neuroinflammation, and their degree of rescue by NLRP3 eficiency. To do so, we will
AβCAR macrophages engineered from Nlrp3 KO or Nlrp3 WT donor mice into the 5xFAD model and
a) the degree to which CAR-augmented Aβ uptake increases macrophage inflammatory profiles and
turn neuroinflammation b) whether this is rescued by Nlrp3 loss, and c) the consequences on Aβ pathology.
2 will improve our understanding of how immunotherapies lead to neuroinflammation and determine whether
inhibition is a strategy to enhance cell therapies for neurodegeneration. Together, these aims will
knowledge gaps about the role of microglial phagocytosis in AD treatment and create a cell-based strategy
specifically target protei...

## Key facts

- **NIH application ID:** 10766740
- **Project number:** 5R01NS129737-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Frederick Bennett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $715,640
- **Award type:** 5
- **Project period:** 2023-01-21 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10766740

## Citation

> US National Institutes of Health, RePORTER application 10766740, Amyloid Beta CAR Macrophages: a cell engineering strategy to clear pathogenic proteins (5R01NS129737-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10766740. Licensed CC0.

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