t cells specifically targeted to amyloid plaques enhance plaque clearance in a mouse model of alzheimers diseaset细胞专门针对淀粉样斑块增强斑块间隙在阿尔茨海默病小鼠模型.pdf

T Cells Specifically Targeted to Amyloid Plaques Enhance Plaque Clearance in a Mouse Model of Alzheimer’s Disease Yair Fisher, Anna Nemirovsky, Rona Baron, Alon Monsonego* The Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, and The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel Abstract Patients with Alzheimer’s disease (AD) exhibit substantial accumulation of amyloid-b (Ab) plaques in the brain. Here, we examine whether Ab vaccination can facilitate the migration of T lymphocytes to specifically target Ab plaques and consequently enhance their removal. Using a new mouse model of AD, we show that immunization with Ab, but not with the encephalitogenic proteolipid protein (PLP), results in the accumulation of T cells at Ab plaques in the brain. Although both Ab-reactive and PLP-reactive T cells have a similar phenotype of Th1 cells secreting primarily IFN-c, the encephalitogenic T cells penetrated the spinal cord and caused experimental autoimmune encephalomyelitis (EAE), whereas Ab T cells accumulated primarily at A b plaques in the brain but not the spinal cord and induced almost complete clearance of Ab. Furthermore, while a single vaccination with Ab resulted in upregulation of the phagocytic markers triggering receptors expressed on myeloid cells-2 (TREM2) and signal regulatory protein-b1 (SIRPb1) in the brain, it caused downregulation of the proinflammatory cytokines TNF-a and IL-6. We thus suggest that Ab deposits in the hippocampus area prioritize the targeting of Ab-reactive but not PLP-reactive T cells upon vaccination. The stimulation of Ab-reactive T cells at sites of Ab plaques resulted in IFN-c-induced chemotaxis of leukocytes and therapeutic cle