A UCLA/Veterans Affairs study has implicated defects in the machinery that creates connections between brain cells as responsible for the onset of Alzheimer disease.

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 study is published in the Nature Neuroscience.

" 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, 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.

The PAK enzymes form a family that includes two members known to localize to synapses ( PAK1 and PAK3 ). Both are known to play critical roles in learning and memory. Humans with genetic loss of PAK3 have severe mental retardation. Both PAK1 and PAK3 are abnormally distributed and reduced in Alzheimer patients to an extent sufficient to contribute to cognitive decline.

The research team found that blocking these PAKs in middle-aged mice causes memory loss together with deficits in a protein involved in making neuronal connections. In humans, the same protein shows large losses in Alzheimer as well as in Down syndrome, the most common cause of mental retardation.

The study also shows in cultures and animal models that Ab42 oligomers induce defects in PAK similar to those seen in Alzheimer disease, and selective loss of the same neuronal connection protein lost in Alzheimer disease and Down syndrome. The findings suggest PAK loss in Alzheimer brains is sufficient to directly cause these cognitive deficits.

Source: University of California - Los Angeles, 2006


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