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Presenilin-1's second role in Alzheimer's
Presenilin-1 (PS-1) is a protein best known for its involvement in cleavage of the amyloid precursor protein, a step that can lead to formation of the brain plaques typical of Alzheimer's disease. Now, a team headed by Nikolaos K. Robakis, a professor in the psychiatry department and in the Center for Neurobiology at Mount Sinai School of Medicine, New York City, has shown that PS-1 has another function [Cell, 114, 635 (2003)]. PS-1 promotes cleavage of neural cadherin (N-cadherin), producing compounds such as N-Cad/CTF2 that are necessary for proper brain-cell function and probably for memory formation. Mutations in the genes that encode PS-1 are associated with many of the early-onset cases of inherited Alzheimer's disease. The researchers show that these mutations lead to the production of PS-1 that is less capable than normal PS-1 of cleaving N-cadherin. That cuts production of N-Cad/CTF2, a compound that promotes degradation of the transcriptional coactivator CBP. Increased CBP concentrations may then damage neurons and synapses, the researchers suggest. They propose that some Alzheimer's cases could be treated with drugs designed to deliver or increase production of N-Cad/CTF2.
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