Public release date: 18-Jan-2011
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Contact: Gina Kirchweger
Kirchweger@salk.edu
858-453-4100, x1340
Salk Institute

Unlocking the secret(ase) of building neural circuits


LA JOLLA, CA—Mutant presenilin is infamous for its role in the most aggressive form of Alzheimer's disease—early-onset familial Alzheimer's—which can strike people as early as their 30s. In their latest study, researchers at the Salk Institute uncovered presenilin's productive side: It helps embryonic motor neurons navigate the maze of chemical cues that pull, push and hem them in on their way to their proper targets. Without it, budding motor neurons misread their guidance signals and get stuck in the spinal cord.

By putting genes associated with Alzheimer's disease in a new light, their findings, published in the Jan. 7, 2011, issue of the journal Cell, reveal an important link between the formation of neural circuits and neurodegenerative disorders. "It was a bit of a surprise since we always thought about presenilin in the context of severing neuronal connections rather than wiring the nervous system during embryonic development," says Howard Hughes Medical Institute investigator Samuel Pfaff, Ph.D., a professor in the Gene Expression Laboratory, who led the study.

Presenilin is a component of the enzyme gamma secretase, which cleaves the amyloid precursor protein, resulting in accumulation of beta amyloid fragments. In Alzheimer's, these fragments form hard, insoluble plaques, one of the hallmarks of the disease.

Many embryonic guidance molecules persist in the adult central nervous system, where they participate in maintenance, repair and plasticity of neural circuits. "This could explain how a deregulation of guidance signaling by abnormal presenilin may play a role in the pathogenesis of Alzheimer's disease," proposes Pfaff.

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http://www.eurekalert.org/pub_releas...-uts011811.php