Enzyme May Protect Against Alzheimer Disease

Higher levels of puromycin-sensitive aminopeptidase found in cerebellum

THURSDAY, Sept. 7 (HealthDay News) -- Higher levels of the enzyme puromycin-sensitive aminopeptidase in the cerebellum may provide protection against abnormal tangles of tau protein that are associated with Alzheimer disease, according to a study in the Sept. 7 issue of Neuron.

Daniel Geschwind, M.D., Ph.D., of the David Geffen School of Medicine at the University of California Los Angeles, and colleagues conducted a microarray analysis of transgenic mice expressing tau to find genes that may be activated more regularly in certain regions of the brain than others. They then performed cross-functional species assessments with fruit flies and studied brain tissue from human patients.

The researchers found that, among the mice, the gene for the enzyme puromycin-sensitive aminopeptidase (PSA) was more active in the cerebellum, a region of the brain that is more resistant to neurodegeneration than the cortex. In the studies with fruit flies, they found PSA overexpression coincided with a loss of tau immunoreactivity. And they found that human PSA can directly degrade human tau in vitro. They also found a fivefold increase in PSA in the cerebellum, compared with the cortex, in samples of brain tissue from both normal humans and those with fibrillary tangle disorders.

"This work provides a clear proof of principle for validation of genetic screens using model systems and allows us to more firmly establish a functional role for one of the identified genes, Psa. Although Psa was known to be highly brain-enriched, to our knowledge, its role vis-a-vis tau degradation or modification of tau-induced neurodegeneration has not been characterized previously," the authors write. "Data derived from in vivo studies with animal models and a cell-free system suggest that PSA may play a pivotal role in protection from tau-induced neurodegeneration, most likely by direct cleavage of tau."

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