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2017 Grants - Jin
Targeting the Microglial Potassium Channel Kv1.3 for the Treatment of AD
Liang Jin, Ph.D.
2017 Alzheimer's Association Research Fellowship (AARF)
Can the release of inflammatory molecules from microglial cells in the brain be blocked to protect nerve cells from damage?
Recent research suggests that Alzheimer's disease involves inflammation in the brain, caused by the overproduction and release of molecules from cells called microglia. Microglia are the immune cells of the brain, and studies have shown that in Alzheimer's disease, accumulation of the protein fragment beta-amyloid stimulates microglia to produce inflammatory molecules that can cause damage to nerve cells. Studies have identified a protein on the surface of microglia, called Kv1.3, that is present in greater numbers in mice that have been genetically engineered to develop an Alzheimer's disease-like condition. The Kv1.3 protein when activated allows potassium to flow through a membrane channel. Microglia with higher amounts of Kv1.3 protein on their surface show greater amounts of cell growth, activity, and production of inflammatory factors; thus, blocking the Kv1.3 has been suggested as a way to reduce inflammation in the brain in Alzheimer's disease.
Liang Jin, Ph.D., and colleagues developed a molecule that can block the Kv1.3 protein without affecting other proteins on the surface of microglial cells. They will examine whether this molecule can block the production and release of inflammatory factors from microglia. Microglia will be grown in a dish in the presence of beta-amyloid to stimulate the production of inflammatory factors, then treated with the Kv1.3 blocker. They will also test the effect of this molecule on microglia that are grown together with nerve cells in a dish in the lab. They will determine whether treatment with the Kv1.3 blocker protects the nerve cells by reducing the release of inflammatory molecules from microglia. Finally, Dr. Jin and colleagues will treat mice that develop an Alzheimer's disease-like condition with the Kv1.3 blocker and measure the effect on memory and learning and the levels of inflammatory molecules in the brain. To do this, they will develop a new system to allow the Kv1.3 blocker to cross from the bloodstream into the brain, to reach the microglia.
This study will evaluate whether blocking a specific protein on the surface of microglial cells can prevent the release of inflammatory factors that damage nerve cells. The proposed work may lead to the development of novel treatments that can reduce inflammation and neuronal damage in the brain to protect or slow the progression of Alzheimer's disease.