Alzheimer disease (AD) is the leading cause of age-related dementia, affecting over 5 million people in the United States alone. Unfortunately, current therapies are largely palliative and several promising drug candidates have failed in late-stage clinical trials. Hence, there is an urgent need to improve our understanding of the basic mechanisms that drive the development of AD and to develop new and effective therapies. Preclinical AD research has thus far relied heavily on transgenic mouse models but recent advances in stem cell biology have opened up an exciting new opportunity to model AD and test therapeutics with patient-derived human cells. Stem cell research is a major strength of the UCI ADRC as we were the first to show improved cognition in transgenic models of AD with neural stem cell transplantation and to use human embryonic stem cells to examine AD-associated mutations. The UCI ADRC therefore proposes the establishment of the first AD induced pluripotent stem (IPS) cell core. The goals of this core will be to generate, validate, and distribute a well-powered collection of AD, MCI, and control IPS cell lines to researchers within the UCI ADRC, within the whole ADC program, and worldwide. The significant advantage of having this core be part of the ADRC is that each cell line is linked to corresponding multi-dimensional clinical, biomarker, and pathological datasets. Hence, the IPS cell will provide scientists with a powerful, novel and innovative approach to understand the genetic and phenotypic basis of sporadic AD and identify and evaluate novel disease-modifying therapeutic interventions. To achieve these goals, the IPS cell core proposes the following 4 specific aims:
AIM 1 : Isolate, expand, and bank primary skin fibroblasts and peripheral blood mononuclear source cells from ADRC clinical cohort subjects.
AIM 2 : Generate integration-free IPS lines from fibroblasts of ADRC subjects.
AIM 3 : Validate, characterize, and expand ADRC iPS cell clones.
AIM 4 : Distribute ADRC iPS cell lines to investigators and facilitate access to corresponding clinical, biomarker, and pathological datasets.
Stem cell research is changing the way we study human disease. The ability to examine disease mechanisms and therapies in primary human cells represents a paradigm shift in preclinical research. Huge strides are indeed being made in the study of human disorders through the use of patient-derived IPS cells. It seems only appropriate that this powerful approach be adopted and incorporated into the ADC Program to study a disease that afflicts so many and for which traditional research avenues have thus far failed.
|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|
|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|
|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|
|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|
|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 :|
|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|
|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|
|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|
|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|
|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|
Showing the most recent 10 out of 452 publications