Elucidating pathways from hereditary Alzheimer mutations to pathological tau phenotypes

Funding Type: 
Basic Biology V
Grant Number: 
Award Value: 
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
Public Abstract: 

We propose to elucidate pathways of genes that lead from early causes to later defects in Alzheimer’s Disease (AD), which is common, fatal, and for which no effective disease-modifying drugs are available. Because no effective AD treatment is available or imminent, we propose to discover novel genetic pathways by screening purified human brain cells made from human reprogrammed stem cells (human IPS cells or hIPSC) from patients that have rare and aggressive hereditary forms of AD. We have already discovered that such human brain cells exhibit an unique biochemical behavior that indicates early development of AD in a dish. Thus, we hope to find new drug targets by using the new tools of human stem cells that were previously unavailable. We think that human brain cells in a dish will succeed where animal models and other types of cells have thus far failed.

Statement of Benefit to California: 

Alzheimer’s Disease (AD) is a fatal neurodegenerative disease that afflicts millions of Californians. The emotional and financial impact on families and on the state healthcare budget is enormous. This project seeks to find new drug targets to treat this terrible disease. If we are successful our work in the long-term may help diminish the social and familial cost of AD, and lead to establishment of new businesses in California using our approaches.

Progress Report: 

The goal of this project has been to understand how neurons made from stem cells that are genetically engineered to develop Alzheimer's disease in a dish generate abnormal biochemistry that we can measure with simple assays. In the first year of this project we developed new probes for the pathway we are trying to measure. However, we encountered technical obstacles that interfere with our ability to evaluate the function of this pathway. We think we have identified the cause of the problems and in the second year of the project we will initiate experiments to solve these problems and rigorously evaluate how genetic mutations that cause abnormal Alzheimer's biochemistry generate the abnormal biochemistry in our human neural system made from stem cells.