Modeling and Drug Screening of AD Using Patients-Derived iPSCs


Identification: Huang, Yadong


Description

Modeling and Drug Screening of AD Using Patients-Derived iPSCs
 
Chengzhong Wang, Ramsey Najm, Yadong Huang
Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Biomedical Sciences Graduate Program and Departments of Neurology and Pathology, University of California, San Francisco, CA, USA
 
Efforts to develop drugs for Alzheimer's disease (AD) have shown promise in animal studies, only to fail in human trials, suggesting a pressing need to study AD in human model systems. Using human neurons derived from induced pluripotent stem cells carrying the major genetic risk factor apolipoprotein E4 (apoE4), we demonstrate that apoE4 neurons have higher levels of tau phosphorylation unrelated to their increased A production and displayed GABAergic neuron degeneration. ApoE4 increased A production in human, but not in mouse, neurons. Converting apoE4 to apoE3 by gene editing rescued these phenotypes, indicating the specific effects of apoE4. Neurons lacking apoE behaved like those expressing apoE3, and introducing apoE4 expression recapitulated the pathological phenotypes, suggesting a gain of toxic effects from apoE4. Interaction between the carboxyl-terminal and the amino-terminal domains, called domain interaction, is a unique biophysical property of apoE4. Domain interaction has been suggested to be a molecular basis for apoE4's detrimental effects in AD pathogenesis, and consequently has been pursued as a drug target to identify small molecule structure correctors capable of converting apoE4 to apoE3 both structurally and functionally. Treating apoE4 neurons with a small-molecule structure corrector ameliorated AD-related detrimental effects, providing a proof of concept that correcting the pathogenic conformation of apoE4 is a viable therapeutic approach for apoE4-related AD.

Credits

Credits: None available.

You must be logged in and own this product in order to post comments.