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2010 Grants - Maezawa
The Role of the Potassium Channel Kv1.3 in AΒ-Induced Microglia Activation
Izumi Maezawa, Ph.D.
University of California, Davis
2010 New Investigator Research Grant
In the brains of people with Alzheimer's disease, the protein fragment beta-amyloid tends to accumulate into clumps called plaques. Much Alzheimer research is devoted to studying ways of clearing beta-amyloid from the brain before it accumulates. Brain cells called microglia act as part of the immune system, clearing various unwanted proteins from the brain—including beta-amyloid. However, microglia also release toxic chemicals that promote brain inflammation, which can both initiate Alzheimer's and hasten its progression. Some investigators believe that an effective Alzheimer therapy should utilize the amyloid clearing ability of microglia, while blocking microglia-induced inflammation.
Izumi Maezawa, Ph.D., and colleagues have been studying microglia in mice engineered to develop Alzheimer-like symptoms. They identified a molecular channel—or series of chemical reactions—that may be involved in activating microglia. Blocking this channel, known as Kv1.3, prevented microglia in the mice brains from causing inflammation without hindering the cells' ability to clear beta-amyloid. For this proposed study, the researchers hope to confirm and expand these promising early results. First, they will compare the expression of Kv1.3 in autopsied brain tissue from people with and without Alzheimer's disease. They will then treat cultured microglia with beta-amyloid aggregates to see if these aggregates stimulate Kv1.3 expression. Finally, using Alzheimer-like mice, the investigators will administer a compound that blocks Kv1.3 activity in the animals. They will then determine whether this compound blocks microglia-related brain inflammation and prevents cognitive decline in the animals.
Results of this study will help elucidate the complex role of microglia in brain disease. The work may also identify a novel Alzheimer therapy for use in human clinical trials.