T cells specifically targeted to amyloid plaques enhance plaque clearance in a mouse model of Alzheimer's disease.
Patients with Alzheimer's disease (AD) exhibit substantial accumulation of amyloid-beta (Abeta) plaques in the brain. Here, we examine whether Abeta vaccination can facilitate the migration of T lymphocytes to specifically target Abeta plaques and consequently enhance their removal. Using a new mouse model of AD, we show that immunization with Abeta, but not with the encephalitogenic proteolipid protein (PLP), results in the accumulation of T cells at Abeta plaques in the brain. Although both Abeta-reactive and PLP-reactive T cells have a similar phenotype of Th1 cells secreting primarily IFN-gamma, the encephalitogenic T cells penetrated the spinal cord and caused experimental autoimmune encephalomyelitis (EAE), whereas Abeta T cells accumulated primarily at Abeta plaques in the brain but not the spinal cord and induced almost complete clearance of Abeta. Furthermore, while a single vaccination with Abeta resulted in upregulation of the phagocytic markers triggering receptors expressed on myeloid cells-2 (TREM2) and signal regulatory protein-beta1 (SIRPbeta1) in the brain, it caused downregulation of the proinflammatory cytokines TNF-alpha and IL-6. We thus suggest that Abeta deposits in the hippocampus area prioritize the targeting of Abeta-reactive but not PLP-reactive T cells upon vaccination. The stimulation of Abeta-reactive T cells at sites of Abeta plaques resulted in IFN-gamma-induced chemotaxis of leukocytes and therapeutic clearance of Abeta.
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.
Yair
Y
Fisher
Anna
A
Nemirovsky
Rona
R
Baron
Alon
A
Monsonego
D000544:Alzheimer Disease / Q000276:immunology* / Q000473:pathology*; D000682:Amyloid / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D001921:Brain / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002465:Cell Movement; D004195:Disease Models, Animal; D007114:Immunization; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018991:Myelin Proteolipid Protein / Q000276:immunology; D058225:Plaque, Amyloid / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D000682:Amyloid; D016229:Amyloid beta-Peptides; D018991:Myelin Proteolipid Protein; D007371:Interferon-gamma