Recently we and others have demonstrated that bone marrow transplantation (BMT) into the APP{swe}/PS1AE9 double transgenic mouse model of Alzheimer's disease (AD) leads to a ~50% reduction in cerebral cortical and hippocampal B-amyloid (AB), 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 APP{swe}/PSI AE9 or wt mice, with or without GFP, into APP{swe}/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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG005136-30
Application #
8459479
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
30
Fiscal Year
2013
Total Cost
$180,062
Indirect Cost
$64,637
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Deming, Yuetiva; Dumitrescu, Logan; Barnes, Lisa L et al. (2018) Sex-specific genetic predictors of Alzheimer's disease biomarkers. Acta Neuropathol 136:857-872
Tulloch, Jessica; Leong, Lesley; Chen, Sunny et al. (2018) APOE DNA methylation is altered in Lewy body dementia. Alzheimers Dement 14:889-894
Tse, Kai-Hei; Cheng, Aifang; Ma, Fulin et al. (2018) DNA damage-associated oligodendrocyte degeneration precedes amyloid pathology and contributes to Alzheimer's disease and dementia. Alzheimers Dement 14:664-679
Kunji, Khalid; Ullah, Ehsan; Nato Jr, Alejandro Q et al. (2018) GIGI-Quick: a fast approach to impute missing genotypes in genome-wide association family data. Bioinformatics 34:1591-1593
Taylor, Laura M; McMillan, Pamela J; Liachko, Nicole F et al. (2018) Pathological phosphorylation of tau and TDP-43 by TTBK1 and TTBK2 drives neurodegeneration. Mol Neurodegener 13:7
Kaur, Antarpreet; Edland, Steven D; Peavy, Guerry M (2018) The MoCA-Memory Index Score: An Efficient Alternative to Paragraph Recall for the Detection of Amnestic Mild Cognitive Impairment. Alzheimer Dis Assoc Disord 32:120-124
Schaffert, Jeff; LoBue, Christian; White, Charles L et al. (2018) Traumatic brain injury history is associated with an earlier age of dementia onset in autopsy-confirmed Alzheimer's disease. Neuropsychology 32:410-416
Flanagan, Margaret E; Larson, Eric B; Walker, Rod L et al. (2018) Associations between Use of Specific Analgesics and Concentrations of Amyloid-? 42 or Phospho-Tau in Regions of Human Cerebral Cortex. J Alzheimers Dis 61:653-662
Brenowitz, Willa D; Han, Fang; Kukull, Walter A et al. (2018) Treated hypothyroidism is associated with cerebrovascular disease but not Alzheimer's disease pathology in older adults. Neurobiol Aging 62:64-71
Tulloch, Jessica; Leong, Lesley; Thomson, Zachary et al. (2018) Glia-specific APOE epigenetic changes in the Alzheimer's disease brain. Brain Res 1698:179-186

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