A new UCLA/Veterans Affairs study implicates 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 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.
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 finds 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.
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Sally Frautschy, associate professor of medicine at the UCLA Geffen School of Medicine and a researcher at the VA’s Geriatric Research Education and Clinical Center, is a co investigator. In addition to UCLA and the VA, the research team included neuroscientists affiliated with Laval University Medical Center in Quebec, Canada, and Osaka University in Japan.
Funding for the study was provided by the VA, the National Institutes of Health, the UCLA Alzheimer Disease Research Center, the UCLA Claude Pepper Older Americans Independence Center and the National Institute of Aging.
A copy of the full study can be found online at http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn1630.html.
The Alzheimer Disease Research Center at UCLA, directed by Dr. Jeffrey L. Cummings, was established in 1991 with a grant from the National Institute on Aging. Together with grants from the Alzheimer’s Disease Research Center of California and the Sidell-Kagan Foundation, the center provides a mechanism for integrating, coordinating and supporting new and ongoing research by established investigators in Alzheimer disease and aging. Information about clinical care and research at the center is available by telephone at (310) 206-3779 or online at http://www.adc.ucla.edu/.
The Department of Neurology at UCLA’s David Geffen School of Medicine encompasses more than a dozen research, clinical and teaching programs. These programs cover brain mapping and neuroimaging, movement disorders, Alzheimer disease, multiple sclerosis, neurogenetics, nerve and muscle disorders, epilepsy, neuro-oncology, neurotology, neuropsychology, headaches and migraines, neurorehabilitation, and neurovascular disorders. The department ranks No. 2 among its peers nationwide in National Institutes of Health funding.
Veterans Affairs Greater Los Angeles Health Care System and Sepulveda Ambulatory Care Center combine resources to form a unified Geriatric Research Education and Clinical Center, one of 20 nationwide. These centers of excellence are designed to improve health care and quality of life to older veterans through the advancement and integration of research, education and clinical achievements in geriatrics and gerontology into the total VA health care system and broader communities.
Additional online resources:
David Geffen School of Medicine at UCLA: http://www.medsch.ucla.edu/.
UCLA Alzheimer Disease Research Center: http://www.adc.ucla.edu/.
VA Geriatric Research, Education and Clinical Center: http://www.grecc-gla.org/mission.htm.
