Yadong Huang and his team focus on the causes and progression of Alzheimer’s disease. Specifically, they study a variant of apolipoprotein E, called apolipoprotein E4 (apoE4). Approximately 60–75 percent of Alzheimer’s patients carry the apoE4 variant, making it the most important genetic risk factor for Alzheimer’s disease. The team uses mouse models and induced pluripotent stem (iPS) cells made from skin cells of patients carrying apoE4 or other mutations related to Alzheimer’s to study their effects on the development, survival, and degeneration of neurons and glial cells. In addition, Huang’s lab is working to identify drug targets, develop therapeutic strategies, and repurpose existing drugs for Alzheimer’s disease and other neurodegenerative disorders.
Disease Areas
Areas of Expertise
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Lab Focus
Research Impact
Huang’s group has made important contributions to understanding how apoE4 causes neuronal deficits and cognitive decline in Alzheimer’s disease. Using genetically engineered mouse models, they showed that human apoE4 is expressed in neurons and causes immune response of glial cells and age-dependent learning and memory impairments, as well as degeneration of GABAergic interneurons in the dentate gyrus, a brain region involved in learning and memory. They also discovered that mice with apoE4 have deficits in hippocampal network activities called sharp-wave ripples, which indicates that a decline of interneuron-enabled slow gamma activity during sharp-wave ripples contributes to apoE4-mediated learning and memory impairments.
The second major effort in Huang’s lab has been to develop better drugs for Alzheimer’s disease. Using human neurons derived from iPS cells, the group demonstrated that those harboring apoE4 have higher levels of tau phosphorylation, increased amyloid beta production, and increased risk of degeneration especially when differentiated into GABAergic interneurons. Huang and his team showed that treating apoE4 neurons with a small-molecule structure corrector ameliorated the detrimental effects, suggesting that correcting the pathogenic conformation of apoE4 is a viable therapeutic approach for apoE4-related Alzheimer’s disease. Huang has also led the Gladstone Center for Translational Advancement on drug repurposing for neurological diseases and identified bumetanide as a potential drug for treating apoE4-related Alzheimer’s disease.