PROJECT 1: ABSTRACT. A key problem in understanding and eventually treating Alzheimer's disease (AD) is our incomplete understanding of the role of genetic risk factors in late-onset, sporadic AD (SAD). While there is no clear single genetic lesion that causes SAD, the observed high heritability suggests that individual genetic background plays a significant role. Here we propose unique applications of human induced pluripotent stem cell (hIPSC) technology to dissect how individual genetic background and identified risk factors predispose to SAD biochemical phenotypes in human neurons and to link that information to clinical data on individual patients and to post-mortem pathology. We are basing our work on our recent finding using hIPSC technology that tested the hypothesis that R haplotypes cause general reduction of SORL1 expression leading to increased amyloid beta (A) peptides and consequent risk of developing SAD [3, 7- 10]. Using hIPSC technology we found that R haplotypes impair a signaling input to the SORL1 gene. Specifically, P haplotypes respond to BDNF by inducing SORL1 expression, while R haplotypes do not. Basal expression levels show no correlation with R or P haplotypes. Thus, the SORL1 genetic contribution to SAD may be caused by complex regulatory variation in living human neurons. We now propose to test our working model for how SORL1 haplotypes contribute to SAD neuronal phenotypes and thus SAD risk in humans in vitro, and in vivo in human patients. We propose to test: 1) the hypothesis that BDNF-induced SORL1 expression modulates amyloidogenic processing of APP and downstream SAD-associated biochemical changes;and 2) the hypothesis that effects of SORL1 haplotype on neuronal phenotypes in vitro are mirrored in clinical data on SAD patients, specifically the relative amounts of BDNF and SORL1 proteins in cerebrospinal fluid (CSF) and post-mortem neuropathological phenotypes. In a related goal, we will investigate whether purified neurons made from our collection of patient hIPSC lines correlates with clinical behavior of individual patients. At present, we have too few hIPSC lines to definitively establish the degree of correlation rigorously, but given the existence of the lines, we will begin to collect comparative data as a way of contributing to future studies. Together, these experiments will provide new data about the details of SORL1 variant contributions to SAD phenotypes in human neurons with differing genetic backgrounds and potentially lead to new pathways for drug discovery and stratification of clinical trials based on genetic background.
Our specific aims are to: 1. Test the hypothesis that the reduced BDNF induction response of purified human neurons with SORL1 risk variant haplotypes enhances SORL1- dependent downstream biochemical SAD phenotypes. 2. To test the hypothesis that the genetic status of patients at the SORL1 locus has a significant influence on clinical phenotypic markers measured in CSF or by post-mortem pathology.

Public Health Relevance

PROJECT 1: GOLDSTEIN - PROJECT NARRATIVE Alzheimer's disease (AD) is common, incurable, and economically and emotionally devastating to families that must cope with its ravages;however, we lack effective therapies for AD in part because of our incomplete understanding of what causes AD in general, and in part because of our limited understanding of the role of genetic risk factors in the causes and progression of AD. Our proposed work takes advantage of recent discoveries we have made using new stem cell technologies that let us make unique human disease in a dish models of AD. We have learned what one important genetic risk factor might do in human neurons, and we propose to extend our findings more deeply and to link our work to the development of disease in defined AD patient populations.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
2P50AG005131-31
Application #
8676147
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4 (J1))
Project Start
2014-04-01
Project End
2019-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
31
Fiscal Year
2014
Total Cost
$157,500
Indirect Cost
$32,500
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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