Chimeric Antigen Receptor Macrophages Target and Resorb Amyloid Plaques in a Mouse Model of Alzheimer's Disease

Pan, Q.; Yan, P.; Kim, A. B.; Xiao, Q.; Haecker, H.; Epelman, S.; Grajales-Reyes, G. E.; Diwan, A.; Lee, J.-M.; DeSelm, C. J.

doi:10.1101/2023.04.28.538637

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bioRxiv · 10.1101/2023.04.28.538637

Chimeric Antigen Receptor Macrophages Target and Resorb Amyloid Plaques in a Mouse Model of Alzheimer's Disease

Pan, Q.·Yan, P.·Kim, A. B.·Xiao, Q.·Haecker, H.·Epelman, S.·Grajales-Reyes, G. E.·Diwan, A.·Lee, J.-M.·DeSelm, C. J.

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Abstract

Substantial evidence suggests a role for immunotherapy in treating Alzheimers disease (AD). Several monoclonal antibodies targeting aggregated forms of beta amyloid (A{beta}), have been shown to reduce amyloid plaques and in some cases, mitigate cognitive decline in early-stage AD patients. We sought to determine if genetically engineered macrophages could improve the targeting and degradation of amyloid plaques. Chimeric antigen receptor macrophages (CAR-Ms), which show promise as a cancer treatment, are an appealing strategy to enhance target recognition and phagocytosis of amyloid plaques in AD. We genetically engineered macrophages to express a CAR containing the anti-amyloid antibody aducanumab as the external domain and the Fc receptor signaling domain internally. CAR-Ms recognize and degrade A{beta} in vitro and on APP/PS1 brain slices ex vivo; however, when injected intrahippocampally, these first-generation CAR-Ms have limited persistence and fail to reduce plaque load. We overcame this limitation by creating CAR-Ms that secrete M-CSF and self-maintain without exogenous cytokines. These CAR-Ms have greater survival in the brain niche, and significantly reduce plaque load locally in vivo. These proof-of-principle studies demonstrate that CAR-Ms, previously only applied to cancer, may be utilized to target and degrade unwanted materials, such as amyloid plaques in the brains of AD mice. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/538637v2_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@561cd6org.highwire.dtl.DTLVardef@17f362forg.highwire.dtl.DTLVardef@be83ecorg.highwire.dtl.DTLVardef@1c735ce_HPS_FORMAT_FIGEXP M_FIG Amyloid targeting CAR Macrophages engineered to secrete M-CSF promote their own local survival and expansion while resorbing amyloid plaques in the brains of Alzheimers disease APP/PS1 mice, resulting in significant local clearance of amyloid plaques of all sizes. C_FIG

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Pan, Q., Yan, P., Kim, A. B., Xiao, Q., Haecker, H., Epelman, S., Grajales-Reyes, G. E., Diwan, A., Lee, J.-M., DeSelm, C. J.. 2023-04-28. Chimeric Antigen Receptor Macrophages Target and Resorb Amyloid Plaques in a Mouse Model of Alzheimer's Disease. https://doi.org/10.1101/2023.04.28.538637

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