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2008 Grants - Di Paolo
Genetic Modulation of PIP2 in Alzheimer's Disease Mouse Models: Effect on Cognitive Decline
Gilbert Di Paolo, Ph.D.
Columbia University Medical Center
New York, New York
2008 New Investigator Research Grant
Beta-amyloid is a protein fragment strongly implicated in the development of Alzheimer pathology. Although large aggregates of beta-amyloid (amyloid plaques) were long suspected of being the toxic form of beta-amyloid, studies in recent years have provided evidence that small aggregates may be the culprit. These small aggregates of a few molecules—beta-amyloid oligomers—appear to cause cognitive deficits and dysfunction of brain synapses, specialized regions of nerve cells that mediate communication between cells. It is not known how beta-amyloid oligomers cause such dysfunction.
Gilbert Di Paolo, Ph.D., and colleagues are studying mechanisms that may explain how beta-amyloid oligomers cause nerve cell dysfunction. They have found that nerve cells exposed to oligomers exhibit decreases in levels of phosphatidylinositol-4,5-bisphosphate (PIP2), a component of the cell mem-brane that plays a key role in cell-to-cell communication. They will examine whether this effect explains beta-amyloid-related synaptic dysfunction.
To address this question, Dr. Di Paolo and colleagues will study mice that have been genetically altered to have less of the protein synaptojanin-1 (Synj1), which eliminates PIP2 at nerve cell synapses. They have found that beta-amyloid oligomers do not reduce PIP2 in nerve cells from these mice. Furthermore, oligomers have much weaker adverse effects on memory-related cell functions in these mice.
The researchers plan to extend their studies to determine if mice with low levels of Synj1 exhibit better preservation of cognitive function when challenged by conditions leading to Alzheimer-like pathology. They will start with mice that express Alzheimer-like pathology and induce additional genetic changes to reduce levels of Synj1. Then the researchers will measure how these changes affect cognitive decline. These studies may help define the mechanisms by which beta-amyloid causes memory impairment.