The same defect in PAK enzyme signaling pathways that causes loss of a vital synapse protein in Down syndrome may contribute to dementias including Alzheimer disease, according to an article published online January 15 by 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, MD, lead author of the study. "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 accumulate 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.

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 the activity of these PAK enzymes in middle-aged mice caused memory loss together with deficits in a protein involved in making neuronal connections. In humans, the same protein shows large losses in Alzheimer disease as well as in Down syndrome, the most common cause of mental retardation.

The study also showed with in vitro work 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 observed cognitive deficits.