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 potenfial treatment for Alzheimer Disease (AD). By generafing and studying induced pluripotent stem cells (iPSCs) form AD and control pafients 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.
|Brenowitz, Willa D; Keene, C Dirk; Hawes, Stephen E et al. (2017) Alzheimer's disease neuropathologic change, Lewy body disease, and vascular brain injury in clinic- and community-based samples. Neurobiol Aging 53:83-92|
|Katsumata, Yuriko; Nelson, Peter T; Ellingson, Sally R et al. (2017) Gene-based association study of genes linked to hippocampal sclerosis of aging neuropathology: GRN, TMEM106B, ABCC9, and KCNMB2. Neurobiol Aging 53:193.e17-193.e25|
|Moga, Daniela C; Abner, Erin L; Wu, Qishan et al. (2017) Bladder antimuscarinics and cognitive decline in elderly patients. Alzheimers Dement (N Y) 3:139-148|
|Shelton, Lindsey B; Baker, Jeremy D; Zheng, Dali et al. (2017) Hsp90 activator Aha1 drives production of pathological tau aggregates. Proc Natl Acad Sci U S A 114:9707-9712|
|Sennik, Simrin; Schweizer, Tom A; Fischer, Corinne E et al. (2017) Risk Factors and Pathological Substrates Associated with Agitation/Aggression in Alzheimer's Disease: A Preliminary Study using NACC Data. J Alzheimers Dis 55:1519-1528|
|Stark, Shauna M; Reagh, Zachariah M; Yassa, Michael A et al. (2017) What's in a context? Cautions, limitations, and potential paths forward. Neurosci Lett :|
|Abud, Edsel M; Ramirez, Ricardo N; Martinez, Eric S et al. (2017) iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases. Neuron 94:278-293.e9|
|Chang, Timothy S; Teng, Edmond; Elashoff, David et al. (2017) Optimizing Effect Sizes With Imaging Enrichment and Outcome Choices for Mild Alzheimer Disease Clinical Trials. Alzheimer Dis Assoc Disord 31:19-26|
|Neu, Scott C; Pa, Judy; Kukull, Walter et al. (2017) Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis. JAMA Neurol 74:1178-1189|
|Kim, Julia; Schweizer, Tom A; Fischer, Corinne E et al. (2017) The Role of Cerebrovascular Disease on Cognitive and Functional Status and Psychosis in Severe Alzheimer's Disease. J Alzheimers Dis 55:381-389|
Showing the most recent 10 out of 452 publications