Haecker, H. | Search bioRxiv

bioRxiv2023

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

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

immunology↗

bioRxiv2019

Microtubules coordinate protrusion-retraction dynamics in migrating dendritic cells

Cells navigating through tissues face a fundamental challenge: while multiple cellular protrusions explore different paths through the complex geometry of an interstitial matrix the cell needs to avoid becoming too long or ramified, which might ultimately lead to a loss of physical coherence. How a cell surveys its own shape to inform the actomyosin system to retract entangled or stretched protrusions is not understood. Here, we demonstrate that spatially distinct microtubule (MT) dynamics regulate amoeboid cell migration by locally specifying the retraction of explorative protrusions. In migrating dendritic cells (DCs), the microtubule organizing center (MTOC) guides the path through a three dimensional (3D) interstitium and local MT depolymerization in protrusions remote from the MTOC triggers myosin II dependent contractility via the RhoA exchange factor Lfc. Depletion of Lfc leads to aberrant myosin localization, thereby causing two effects that rate-limit locomotion: i) impaired cell edge coordination during path-finding and ii) defective adhesion-resolution. Such compromised cell shape control is particularly hindering when cells navigate through geometrically complex microenvironments, where it leads to entanglement and ultimately fragmentation of the cell body. Our data demonstrate that MTs control cell shape and coherence by locally controlling protrusion-retraction dynamics of the actomyosin system.

cell biology↗