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 (A beta) plaques in the brain. Here, we examine whether A beta vaccination can facilitate the migration of T lymphocytes to specifically target A beta plaques and consequently enhance their removal. Using a new mouse model of AD, we show that immunization with A beta, but not with the encephalitogenic proteolipid protein (PLP), results in the accumulation of T cells at A beta plaques in the brain. Although both A beta-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 A beta T cells accumulated primarily at A beta plaques in the brain but not the spinal cord and induced almost complete clearance of A beta. Furthermore, while a single vaccination with A beta resulted in upregulation of the phagocytic markers triggering receptors expressed on myeloid cells-2 (TREM2) and signal regulatory protein-beta 1 (SIRP beta 1) in the brain, it caused downregulation of the proinflammatory cytokines TNF-alpha and IL-6. We thus suggest that A beta deposits in the hippocampus area prioritize the targeting of A beta-reactive but not PLP-reactive T cells upon vaccination. The stimulation of A beta-reactive T cells at sites of A beta plaques resulted in IFN-gamma-induced chemotaxis of leukocytes and therapeutic clearance of A beta.