For many neurological disorders including Alzheimer Disease (AD), current therapies are largely palliative and based on small molecule designs. However, studies have begun to examine the use of stem cells to both treat and model neurodegenerative disease. Although stem cells have been suggested as a potenfial therapy for AD, to date this approach has not been directly tested in animal models. Consequenfiy, it is critical to obtain pre-clinical evidence to determine whether neural stem cell (NSC) transplantation can offer symptomafic or disease-modifying effects for AD. In preliminary studies, we have found that short-term transplantation of murine NSCs into aged triple transgenic mice (3xTg-AD) improves cognitive function. Interesfingly, NSCs rescue cognifion not by differentiating into neurons or altering levels of AB or tau, but rather by increasing levels of brain-derived neurotrophic factor and enhancing endogenous hippocampal synaptic connectivity. These initial findings suggest that NSC transplantation may provide a promising therapeutic approach. However, AD manifests as a long-term and progressive illness. Thus, it is critical to determine whether NSC transplantation can provide benefits across an extended duration. Here we propose to perform a longitudinal examinafion of the effect of NSC transplantation on AD-related cognitive function in 3xTg-AD mice. We hypothesize that the long-term effectiveness of NSC-based therapies can be improved upon by combining both trophic and disease-modifying approaches. Thus, we will also examine whether NSCs engineered to express an AB-degrading enzyme can provide more substanfial long-term benefit. In addition to their potential therapeutic use, stem cells are being actively studied as a novel and powerful approach to model human disease. To begin to examine the use of stem cells to model AD we therefore propose to generate induced pluripotent stem cells (iPSCs) from AD and control patient fibroblasts Comparisons of AB and tau and their various assembly and phosphorylation states will determine whether genetic factors influence the production, oligomerization, or degradation of these proteins. Likewise analysis of the survival of iPSC-derived neurons in response to AB oligomer treatment will be examined to determine whether AD iPSC-derived neurons are innately more suscepfible to disease-related insults.
The proposed studies build upon our preliminary data to investigate the long-term benefit of neural stem cell transplantation as a potential treatment for Alzheimer Disease (AD). By generating and studying induced pluripotent stem cells (iPSCs) form AD and control patients we will also begin to examine the utility of stem cells to model sporadic AD. The proposed studies thus have relevance to both the potential future treatment and future study of AD.
|John, Samantha E; Gurnani, Ashita S; Bussell, Cara et al. (2016) The effectiveness and unique contribution of neuropsychological tests and the Î´ latent phenotype in the differential diagnosis of dementia in the uniform data set. Neuropsychology 30:946-960|
|Bonham, Luke W; Geier, Ethan G; Fan, Chun C et al. (2016) Age-dependent effects of APOE Îµ4 in preclinical Alzheimer's disease. Ann Clin Transl Neurol 3:668-77|
|Paganini-Hill, Annlia; Kawas, Claudia H; Corrada, Maria M (2016) Lifestyle Factors and Dementia in the Oldest-old: The 90+ Study. Alzheimer Dis Assoc Disord 30:21-6|
|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|
|Ting, Simon Kang Seng; Hao, Ying; Chia, Pei Shi et al. (2016) Clinicopathological correlation of psychosis and brain vascular changes in Alzheimer's disease. Sci Rep 6:20858|
|Chapman, Kimberly R; Bing-Canar, Hanaan; Alosco, Michael L et al. (2016) Mini Mental State Examination and Logical Memory scores for entry into Alzheimer's disease trials. Alzheimers Res Ther 8:9|
|Grill, Joshua D; Zhou, Yan; Elashoff, David et al. (2016) Disclosure of amyloid status is not a barrier to recruitment in preclinical Alzheimer's disease clinical trials. Neurobiol Aging 39:147-53|
|Leal, Stephanie L; Noche, Jessica A; Murray, Elizabeth A et al. (2016) Positivity effect specific to older adults with subclinical memory impairment. Learn Mem 23:415-21|
|Fischer, Corinne E; Qian, Winnie; Schweizer, Tom A et al. (2016) Lewy Bodies, Vascular Risk Factors, and Subcortical Arteriosclerotic Leukoencephalopathy, but not Alzheimer Pathology, are Associated with Development of Psychosis in Alzheimer's Disease. J Alzheimers Dis 50:283-95|
|Jun, G; Ibrahim-Verbaas, C A; Vronskaya, M et al. (2016) A novel Alzheimer disease locus located near the gene encoding tau protein. Mol Psychiatry 21:108-17|
Showing the most recent 10 out of 383 publications