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2016 Grants - Lim
Deciphering the Role of SYK as a Key Mediator of ABeta Clearance by Microglia
Siok Lam (Sharon) Lim, Ph.D.
University of California, Irvine
2016 Alzheimer’s Association Research Fellowship (AARF)
How do alterations in an immune-related protein affect the clearance of beta-amyloid from the brain?
Characteristic features of Alzheimer’s disease in the brain include the build-up of the protein fragment beta-amyloid into amyloid plaques and excessive inflammation. There is increasing evidence that these processes are related, but the underlying mechanisms are not well understood. Inflammation is the normal response of the body to infection or injury and is normally turned off after the condition is resolved. In Alzheimer’s disease, however, inflammation in the brain remains high, possibly contributing to disease progression.
Inflammation is mediated by the immune system, and the main cells of the immune system in the brain are known as microglia. Microglia may become “overactive” during Alzheimer’s disease leading to excessive inflammation. Microglia are also important for clearing beta-amyloid from the brain, but when they become overactivated this function may be impaired.
Siok Lam (Sharon) Lim, Ph.D., and colleagues will study what controls the activation of microglia and their ability to clear beta-amyloid from the brain. Their work will focus on a protein known as SYK (spleen tyrosine kinase), which is thought to be involved in controlling the activation state of microglia. The researchers will use microglia growing in laboratory dishes to test how SYK affects the cells’ activation state and ability to clear beta-amyloid. They will also study mice genetically-engineered to lack the SYK protein on their microglia to determine how this impacts brain inflammation, accumulation of beta-amyloid and nerve cell health.
These studies may increase our understanding of the molecular mechanisms that link inflammation and beta-amyloid accumulation in the brain. Importantly, these findings could identify new ways to regulate microglia and potentially restore the brain’s ability to clear beta-amyloid to slow or prevent Alzheimer’s disease.