Role of Neurexins in Alzheimer's Disease
MentorDora Kovacs, PhD Massachusetts General Hospital
The severity of Alzheimer's disease (AD) symptoms is directly linked to levels of the amyloid beta (i.e., the generation of Abeta peptide), as shown by genetic studies. Abeta levels and the amount of amyloid deposits increase in AD, yet factors that increase Abeta levels at the synapses (the connections between nerve cells) remain largely unknown. The goal of this project is to study the role of a type of synapse protein, called Neurexins, in regulating amyloid deposition in AD. Collectively, this research proposal will provide novel insights into the development and progression of Alzheimer's disease.
The laboratory of Drs. Gautam and Kovac recently identified the Neurexin family of proteins as a novel type of interacting partners for Amyloid Precursor Protein (APP), a protein that generates toxic Abeta peptide in the brain. Functional relevance of this interaction is underscored by the result that reducing the expression level of Neurexin significantly increases toxic Abeta levels in neurons. As expression of different forms of Neurexin in different brain regions is highly age-dependent, regulated interaction between APP and Neurexins may regulate synaptic Abeta generation. Here, the team of Drs. Gautam and Kovac is testing the hypothesis that Neurexin represses Abeta generation in the brain by interacting with APP in a regulated manner. For this purpose, the team is studying the mechanism of how Neurexins modulate APP metabolism and Abeta generation in cultured nerve cells. The results of these studies may help to understand the initiation and progression of Alzheimer's disease, and may contribute to the development of novel strategies for the prevention and treatment of the disease.