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

Autor:	Pan Q; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA., Yan P; Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA., Kim AB; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.; Bursky Center for Human Immunology and Immunotherapy, Washington University School of Medicine, St. Louis, MO, USA., Xiao Q; Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA., Pandey G; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.; Bursky Center for Human Immunology and Immunotherapy, Washington University School of Medicine, St. Louis, MO, USA., Haecker H; Department of Pathology, University of Utah, Salt Lake City, UT, USA., Epelman S; Department of Medicine, Division of Cardiology, Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada., Diwan A; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.; Medicine Service, Saint Louis VA Medical Center, St. Louis, MO, USA.; Departments of Medicine, Cell Biology and Physiology, Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri, USA., Lee JM; Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA., DeSelm CJ; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.; Bursky Center for Human Immunology and Immunotherapy, Washington University School of Medicine, St. Louis, MO, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 May 03. Date of Electronic Publication: 2023 May 03.
DOI:	10.1101/2023.04.28.538637
Abstrakt:	Substantial evidence suggests a role for immunotherapy in treating Alzheimer's disease (AD). Several monoclonal antibodies targeting aggregated forms of beta amyloid (Aβ), 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 Aβ 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.
Databáze:	MEDLINE
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