Recently we and others have demonstrated that bone marrow transplantation (BMT) into the APPswe/PS1AE9 double transgenic mouse model of Alzheimer's disease (AD) leads to a ~50% reduction in cerebral cortical and hippocampal p-amylold (Ap), both soluble and in plaques. We hypothesize that nonmyeloablative or "mini" BMT will be a safe and effective therapy for the treatment of AD, and hypothesize that its efficacy can be enhanced by genetic manipulation of the donor cells. To that end, the Specific Aims in this application focus on effects of BMT and reduced AB on measures of neurotoxicity, on mechanisms of AB reduction, and on approaches to reduce preconditioning toxicity and to enhance transplant efficacy.
In Specific Aim 1, we test the hypothesis that BMT-mediated AB reduction is due to an immune response of self to non-self by transplanting cells from APPswe/PSI AE9 or wt mice, with or without GFP, Into APPswe/PS1AE9 mice. The results will provide critical information relevant not only to mechanisms of AB reduction but that may guide the clinical application of this technology (allogeneic vs. autologous grafts).
In Specific Aim 2, we test the hypothesis that genetic manipulation of donor cells can be performed to enhance efficacy of the therapy, by transplanting BM from mice that lack prostaglandin receptor EP2, which is integral to control of microglial phagocytosis and paracrine neurotoxicity. In our preliminary data we have shown that BMT with donor EP2-/-mice leads to a further significant reduction in cortical AB plaques, but we wish to expand on these experiments by examining soluble AB and associated neurotoxicity. Results of these experiments may guide future work into genetic manipulation of allogeneic or even autologous BM to customize treatments based on disease and host. Finally, since myeloablative preconditioning for BMT is associated with significant toxicity, in our third Specific Aim we test that hypothesis that BMT in mice with non-myeloablative preconditioning will also result in decreased AB, which will be critical in future clinical application in elderly patients. In each of the Specific Aims we correlate changes in AB with measures of neurotoxicity. The translational experiments proposed herein will lay the groundwork for possible future applications of BMT for AD and other neurodegenerative diseases.
Currently no efficacious therapy for Alzheimer's disease exists. This application is focused on testing the potential for a novel therapy for AD, bone marrow transplantation. Results from these experiments will further our understanding of the mechanisms of BMT in AD, whether this therapy is protective of the brain, and whether the use of genetically altered bone marrow can enhance the effects. Results of these experiments will lay the foundation for a potentially powerful and effective new treatment for AD.
|Ridge, Perry G; Hoyt, Kaitlyn B; Boehme, Kevin et al. (2016) Assessment of the genetic variance of late-onset Alzheimer's disease. Neurobiol Aging 41:200.e13-20|
|Toledo, Jon B; Gopal, Pallavi; Raible, Kevin et al. (2016) Pathological Î±-synuclein distribution in subjects with coincident Alzheimer's and Lewy body pathology. Acta Neuropathol 131:393-409|
|Ringman, John M; Monsell, Sarah; Ng, Denise W et al. (2016) Neuropathology of Autosomal Dominant Alzheimer Disease in the National Alzheimer Coordinating Center Database. J Neuropathol Exp Neurol 75:284-90|
|Brenowitz, Willa D; Hubbard, Rebecca A; Keene, C Dirk et al. (2016) Mixed neuropathologies and estimated rates of clinical progression in a large autopsy sample. Alzheimers Dement :|
|Besser, Lilah M; Alosco, Michael L; Ramirez Gomez, Liliana et al. (2016) Late-Life Vascular Risk Factors and Alzheimer Disease Neuropathology in Individuals with Normal Cognition. J Neuropathol Exp Neurol 75:955-962|
|Crane, Paul K; Gibbons, Laura E; McCurry, Susan M et al. (2016) Importance of home study visit capacity in dementia studies. Alzheimers Dement 12:419-26|
|Burke, Shanna L; Maramaldi, Peter; Cadet, Tamara et al. (2016) Neuropsychiatric symptoms and Apolipoprotein E: Associations with eventual Alzheimer's disease development. Arch Gerontol Geriatr 65:231-8|
|Beckelman, Brenna C; Zhou, Xueyan; Keene, C Dirk et al. (2016) Impaired Eukaryotic Elongation Factor 1A Expression in Alzheimer's Disease. Neurodegener Dis 16:39-43|
|Henderson, Benjamin W; Gentry, Erik G; Rush, Travis et al. (2016) Rho-associated protein kinase 1 (ROCK1) is increased in Alzheimer's disease and ROCK1 depletion reduces amyloid-Î² levels in brain. J Neurochem 138:525-31|
|Tosto, Giuseppe; Monsell, Sarah E; Hawes, Stephen E et al. (2016) Progression of Extrapyramidal Signs in Alzheimer's Disease: Clinical and Neuropathological Correlates. J Alzheimers Dis 49:1085-93|
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