The defect in PAK enzyme signaling pathways -- vital to creation of these connections, or synapses -- is related to loss of a synapse protein in certain forms of mental retardation, such as Down syndrome. The new finding suggests therapies designed to address the PAK defect could treat cognitive problems in both patient populations.

The peer-reviewed journal Nature Neuroscience published the study online Jan. 15.

"The emerging lesson is that cognitive problems in Alzheimer disease are related to defects in the machinery controlling neuronal connections, not the lesions observed by pathologists," said principal investigator Greg Cole, professor of medicine and neurology at the David Geffen School of Medicine and Alzheimer Disease Research Center at UCLA, and the Geriatric Research Education and Clinical Center at the Veterans Affairs Greater Los Angeles Health Care System and Sepulveda Ambulatory Care Center. "Our findings show that PAK defects in the brains of Alzheimer patients appear sufficient to directly cause cognitive difficulties."

In some families, early-onset Alzheimer disease can be caused by mutations in different genes that all increase the production of a sticky protein called Abeta42 (Ab42). The increase causes the protein to form aggregates, little clusters or long filaments that pile up and make lesions in the brain called plaques.

Ab42 is widely believed to cause Alzheimer, but the process remains unclear. Soluble Ab42 aggregates called "oligomers" are now considered as a major toxic form of Ab42 and therefore implicated in loss of synapses and memory.

This new study implicates the PAK enzyme-signaling pathway, which is known to play a role in synapse formation and developmental cognitive deficits, or mental retardation.

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Contact: Dan Page
dpage@mednet.ucla.edu
310-794-2265
University of California - Los Angeles
26-Jan-2006