We recently described the directed conversion of human skin fibroblasts from unaffected individuals and Alzheimer's disease (AD) patients to a CNS neuron phenotype, termed human induced neuronal cells (hiN) 1. Herein we propose to further develop hiN cells as tools for AD modeling, and subsequently to validate the approach in a more detailed analysis of cellular mechanisms of AD. The focus of the proposed studies is on familial AD (FAD)-associated disease with defined genetic lesions in presenilin-1 (PSEN1) or presenilin-2 (PSEN2). A clear advantage of such an analysis of FAD with defined mutations is that this facilitates genetic 'rescue'studies, as well as genetic dissection of function. Yet ultimately, perhaps the most exciting aspect of the hiN cell technology is that it may permit a cellular analysis of 'sporadic'disease. The overarching hypotheses to be tested in this work are that cellular aspects of FAD pathophysiology are: (1) Cell-autonomous to neurons and maintained through epigenetic reprogramming, and therefore amenable to hiN cell modeling. (2) Include altered intracellular vesicular trafficking at the soma and the synapse. The proposed deliverables for this proposed work are: (1) Novel human neuronal cell models for dissection of AD mechanisms and drug screening. (2) Directed reprogramming tools that may be broadly applied to the study of neurological disease.

Public Health Relevance

We describe a novel approach to the generation of human neurons by the directed conversion of human skin cells. Such neurons, when derived from patients with familial forms of Alzheimer's, show pathological changes that typify the disease. Here we propose to investigate the mechanism by which human Alzheimer patient neurons develop cellular and molecular deficits.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG042317-02
Application #
8516947
Study Section
Special Emphasis Panel (ZRG1-MDCN-T (91))
Program Officer
Wise, Bradley C
Project Start
2012-08-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$468,193
Indirect Cost
$157,282
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Rhinn, Herve; Fujita, Ryousuke; Qiang, Liang et al. (2013) Integrative genomics identifies APOE ?4 effectors in Alzheimer's disease. Nature 500:45-50