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2012 Grants - Meli
Targeting Subcellular Beta-Amyloid Oligomers in Human Alzheimer's Primary Cells
Giovanni Meli, Ph.D.
European Brain Research Institute
2012 New Investigator Research Grant
During the earliest stages of Alzheimer's disease, the protein fragment beta-amyloid begins to accumulate into toxic clumps or aggregates within the brain. One early type of beta-amyloid aggregate, called the oligomer, contains only a few amyloid molecules. Yet oligomers are now considered among the most toxic forms of the protein. These aggregates have been shown to target synapses, the tiny channels through which brain cells communicate with one another. Oligomer-induced synaptic damage can lead to the cognitive loss and brain cell damage characteristic of Alzheimer's. Research suggests that amyloid oligomers begin forming within neurons, but the exact mechanisms by which this early formation takes place are unknown.
Giovanni Meli, Ph.D., and colleagues have devised a novel method for studying how oligomers form within neurons. They have developed oligomer "antibodies" that can prevent oligomer formation in cultured brain cells. These antibodies have been designed so that they are generated within the cells and will target only amyloid oligomers—not individual amyloid molecules.
Dr. Meli and colleagues will apply their antibody tool in certain types of neurons. These neurons will have been genetically "re-engineered" from fibroblasts (or connective tissue cells) that were taken from people with Alzheimer's disease. Such brain cells provide scientists with an effective model for analyzing brain changes in human dementia. The researchers will introduce their antibodies into various components within the engineered neurons, including the protein- and energy-producing compartments called the endoplasmic reticulum and the mitochondria. They will then assess how their antibody treatment prevents oligomer formation in these "subcellular" regions. Results of Dr. Meli's work could shed new light on how oligomers are produced in early Alzheimer's. They could also lead to novel therapies for preventing the disorder.