2011 Grants - Pahan

TLR2, a New Therapeutic Target for Microglial Activation in Alzheimer's Disease

Kalipada Pahan, Ph.D.
Rush University Medical Center
Chicago, IL

2011 Investigator – Initiated Research Grant

Microglia are a type of cell in the brain that perform many of the functions of the immune system. They also secrete hormone-like compounds that promote the survival of nerve cells. However, microglia can become excessively activated, leading to inflammation and damage in the brain. Indeed, excessive activation of microglia is a characteristic feature of Alzheimer's disease.

The mechanisms of microglia activation in Alzheimer's disease are not well understood, but it has been shown that they are activated by beta-amyloid, a protein fragment that is the main component of amyloid plaques. In recent years, scientists have characterized some of the proteins on the surface of microglia that recognize beta-amyloid. These proteins are known as the toll-like receptors (TLRs), and they are important for activation of the immune system during infection.

Kalipada Pahan, Ph.D, and colleagues have found that signaling through a specific TLR, TLR2, is essential for activation of microglia by beta-amyloid, even though beta-amyloid does not directly bind to TLR2. They have proposed a series of molecular studies to determine the proteins on the surface of microglial cells that couple the binding of beta-amyloid to the TLR2 signaling pathway. They also plan to develop a drug-like compound that inhibits the TLR2 signaling pathway to test its ability to suppress excessive activation of microglia. These studies will advance our understanding of a key molecular pathway involved in brain inflammation in people with Alzheimer's disease.