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2017 Grants - Avila
The Role of Microglial CD33 on Amyloid Deposition and Synaptic Pathology
Alejandro Avila, Ph.D.
New York University School of Medicine
New York, New York
2017 Alzheimer’s Association Research Fellowship to Promote Diversity (AARF-D)
How might an immune system gene in the brain promote the development of beta-amyloid plaques in Alzheimer’s disease?
Beta amyloid is a protein fragment that tends to accumulate into harmful clumps called plaques in the brains of people with Alzheimer’s disease. These clumps may contribute to memory loss and other cognitive problems in Alzheimer’s, but scientists have not yet identified the exact biological mechanism through which plaques produce their toxicity.
Amyloid plaques tend to attract cells of the immune system called microglia. Recent studies have found that a genetic variant of the gene known as cluster of differentiation 33 (CD33) may be linked to beta-amyloid clumping and increased Alzheimer’s risk. Moreover, the elimination of CD33, which is highly expressed in microglia, has been shown to reduce plaque levels. These findings suggest that microglial CD33 may help foster plaque development in Alzheimer’s disease. However, the CD33 gene is also expressed in neurons and monocytes, another group of immune system cells known to cluster around amyloid plaques. This complex molecular environment makes it difficult for researchers to determine how microglial CD33 specifically affects plaque formation and brain cell damage in living brains.
To overcome this problem, Alejandro Avila, Ph.D., and colleagues will genetically engineer a mouse model in which microglial CD33 activity can be examined over time. They will then use sophisticated microscopy techniques to peer into the brain to determine the precise function of this gene in beta-amyloid clumping and damage to synapses—the tiny specialized structure through which brain cells communicate with one another. Synaptic damage has been shown to promote brain cell dysfunction and ultimately cell loss in Alzheimer’s disease.
Dr. Avila’s project could identify an important molecular factor underlying the brain changes that lead to Alzheimer’s disease onset. It could also lead to novel therapeutic strategies for Alzheimer’s that target microglia and CD33 function.