Alzheimer's disease is a complex, multifactorial syndrome characterized clinically by early learning and memory deficits that progress into a severe and as-of-yet irreversible dementia. The vast majority of cases occur sporadically, and age and genetics are the strongest risk factors for onset. The APOE gene is the most strongly associated with the development and clinical progression of sporadic AD. The molecular dynamics of APOE are complex due to differential effects of allelic isoform and synthesis and secretion by multiple cell types. To unravel this complexity, our laboratory has generated induced pluripotent stem cells from patients with sporadic AD. Though the majority of APOE in the brain is produced by astrocytes, previous findings from our lab demonstrated an association of APOE genotype with AD-relevant phenotypes in human basal forebrain cholinergic neurons - a cell population which dies early in AD. Limited information is available about the role of neuronal APOE in neurodegenerative change. This proposal will therefore test the hypothesis that APOE isoform exerts cell autonomous effects in cholinergic neurons that result in altered amyloid processing (Aim 1) and calcium homeostasis (Aim 2). Our findings in this novel human cellular model of genetic risk in sporadic AD will build upon insight from previous rodent and human clinical studies while providing unprecedented experimental control of gene isoform and cell type of expression. The proposed studies will clarify the multiple roles of APOE in human neural cells and identify critical intersections with proposed molecular mechanisms for AD. In doing so, we aim to develop strategies for earlier diagnosis and more successful intervention of this debilitating disease.

Public Health Relevance

Alzheimer's disease causes memory difficulties that make it challenging for a patient to care for him or herself, and though its cause is not known, certain genes can increase the risk of developing it. We will make stem cells from patients whose genes either increase or decrease their risk of developing Alzheimer's disease. In the laboratory, these cells can be transformed into the brain cells that die in this disorder, and can be used to identify new ways to slow or prevent the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30AG051327-01A1
Application #
9121316
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Yang, Austin Jyan-Yu
Project Start
2016-05-01
Project End
2018-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Neurology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611