Degree Granting Department
Gary Arendash, Ph.D.
Immunotherapy, T cell, Behavior, Transgenic mouse, Neurodegenerative diseases
One major therapeutic target for preventing and treating Alzheimer's Disease (AD) is removal of excess beta-amyloid from the brain. Both active and passive immunotherapies targeting beta-amyloid have proven effective in reducing brain beta-amyloid levels and improving cognitive function in mouse transgenic models of AD. However, these approaches can induce adverse neuropathologic effects and immunologic over-activation. Indeed, clinical trials of active beta-amyloid immunotherapy in AD patients were halted due to development of meningoencephalitis, apparently resulting from wide-spread neuroinflammation. Here we show that a more restricted and specific immune re-activation through a single adoptive transfer of beta-amyloid-specific T cells can provide long-term benefits to APPsw+PS1 transgenic mice that last at least 1 1/2 months. beta-amyloid-sensitive splenocytes and lymphocytes were generated in normal mice, re-stimulated with beta-amyloid in vitro, and then adoptive
ly transferred into cognitively-impaired APPsw+PS1 mice. Compared to control transgenic mice through 1 1/2 month post-infusion, those mice that received beta-amyloid-sensitive T cells exhibited a reversal of pre-infusion working memory impairment and demonstrated superior basic mnemonic processing. Step-wise forward Discriminant Function Analysis of behavioral results clearly demonstrated that T cell infused mice performed comparably to wild-type non-transgenics, further emphasizing the extent of cognitive benefit this therapeutic technique afforded. Importantly, a global inflammatory response did not accompany these benefits. Though no overall reductions in beta-amyloid deposition were noted for T cell recipient mice, a subset of T cell infused mice that benefited most in cognitive function had reduced hippocampal burdens, suggesting that hippocampal beta-amyloid burdes did play a role in determining performance capabilities of these mice. Since chronically high levels of beta-amy
loid such as those found in APPsw+PS1 mice cause immune hypo-responsive/tolerance to beta-amyloid, our results indicate that adoptive transfer of beta-amyloid-sensitive T-cells can supercede such immune tolerance to beta-amyloid, and may provide a safe, long-lasting therapy for AD.
Scholar Commons Citation
Shippy, Daniel, "Effects of adoptive transfer of beta-amyloid sensitive immune cells in a mouse model for Alzheimer's disease" (2005). Graduate Theses and Dissertations.