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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
3P50AG016573-14S1
Application #
8668862
Study Section
National Institute on Aging Initial Review Group (NIA)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
14
Fiscal Year
2013
Total Cost
$46,387
Indirect Cost
$15,967
Name
University of California Irvine
Department
Type
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Torres, Maria D; Garcia, Octavio; Tang, Cindy et al. (2018) Dendritic spine pathology and thrombospondin-1 deficits in Down syndrome. Free Radic Biol Med 114:10-14
Burke, Shanna L; Maramaldi, Peter; Cadet, Tamara et al. (2018) Decreasing hazards of Alzheimer's disease with the use of antidepressants: mitigating the risk of depression and apolipoprotein E. Int J Geriatr Psychiatry 33:200-211
Qian, Winnie; Fischer, Corinne E; Schweizer, Tom A et al. (2018) Association Between Psychosis Phenotype and APOE Genotype on the Clinical Profiles of Alzheimer's Disease. Curr Alzheimer Res 15:187-194
Largent, Emily A; Karlawish, Jason; Grill, Joshua D (2018) Study partners: essential collaborators in discovering treatments for Alzheimer's disease. Alzheimers Res Ther 10:101
Gallagher, Damien; Kiss, Alex; Lanctot, Krista et al. (2018) Depression and Risk of Alzheimer Dementia: A Longitudinal Analysis to Determine Predictors of Increased Risk among Older Adults with Depression. Am J Geriatr Psychiatry 26:819-827
Miranda, Andre M; Herman, Mathieu; Cheng, Rong et al. (2018) Excess Synaptojanin 1 Contributes to Place Cell Dysfunction and Memory Deficits in the Aging Hippocampus in Three Types of Alzheimer's Disease. Cell Rep 23:2967-2975
Haaksma, Miriam L; Calderón-Larrañaga, Amaia; Olde Rikkert, Marcel G M et al. (2018) Cognitive and functional progression in Alzheimer disease: A prediction model of latent classes. Int J Geriatr Psychiatry 33:1057-1064
Ramsey, Christine M; Gnjidic, Danijela; Agogo, George O et al. (2018) Longitudinal patterns of potentially inappropriate medication use following incident dementia diagnosis. Alzheimers Dement (N Y) 4:1-10
Melikyan, Zarui A; Greenia, Dana E; Corrada, Maria M et al. (2018) Recruiting the Oldest-old for Clinical Research. Alzheimer Dis Assoc Disord :
Hadjichrysanthou, Christoforos; McRae-McKee, Kevin; Evans, Stephanie et al. (2018) Potential Factors Associated with Cognitive Improvement of Individuals Diagnosed with Mild Cognitive Impairment or Dementia in Longitudinal Studies. J Alzheimers Dis 66:587-600

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