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Apr 2, 2010

Approved Immunosuppressant Found to Be Effective in Mouse Model of Alzheimer Disease

  • Rapamycin, an approved immunosuppressant, improved learning and memory in a strain of mice engineered to develop Alzheimer disease (AD), according to researchers at The University of Texas Health Science Center at San Antonio. The improvements were detected in a water maze activity test and correlated with lower damage in brain tissue. The study is published in Public Library of Science.

    The scientists engineered a strain of mice to have defects in the genes that make amyloid precursor protein, ultimately resulting in the abnormal accumulation of amyloid-beta-42 that dampens synaptic connections. “Rapamycin treatment lowered levels of amyloid-beta-42, a major toxic species of molecules in Alzheimer disease,” says Veronica Galvan, Ph.D., assistant professor from the Sam and Ann Barshop Institute for Longevity and Aging Studies at The University of Texas.

    This marks the second report linking rapamycin to AD treatment within the last month or so. The previous study, published February 23 in The Journal of Biological Chemistry (JCB), highlighted an interrelation between mammalian target of rapamycin (mTOR) signaling and A-beta.  Using a different animal model of AD, the group found that pharmacologically restoring mTOR signaling with rapamycin rescues cognitive deficits and ameliorates A-beta and tau pathology by increasing autophagy.

    Additionally, in July 2009, a different group of Barshop Institute researchers and colleagues at two other institutions reported that microencapsulated rapamycin extended the life span of mice, possibly by delaying aging. A bacterial product first isolated from Easter Island soil, rapamycin is sanction by the FDA to prevent organ rejection in transplant patients.

    In the current research, the same rapamycin-supplemented diet as they used in the life-span study was fed to groups of AD-susceptible mice and their normal littermates. A nonrapamycin diet was fed to control groups. Rapamycin feeding began at four months of age, when the susceptible mice show high amyloid-beta-42 levels and synaptic dysfunction but do not yet have amyloid beta plaques or spatial memory impairments.

    After 13 weeks of treatment, all groups were trained in the water maze exercise to see how quickly they could learn to exit the water via a hidden platform. The AD model mice that were fed the control diet predictably showed significant losses in learning and memory and reduced performance.

    “Strikingly, the Alzheimer's mice treated with rapamycin displayed improved performance on the maze, even reaching levels that were indistinguishable from their normal littermates,” Dr. Galvan said. “Levels of amyloid-beta-42 were also reduced in these mice after treatment, and we are seeing preserved numbers of synaptic elements in the brain areas of Alzheimer's disease mice that are ravaged by the disease process.”

    Additionally, differences in resistance to swimming in the middle of the pool (a measure of anxiety) and in floating (a measure of hopelessness) were not observed among groups. “This suggests that improved performance in rapamycin-treated, Alzheimer's-susceptible mice is a result of effects on purely cognitive processes but is not due to effects related to noncognitive components of behavior, such as helplessness and anxiety,” Dr. Galvan explains.

    “The fact that we are seeing identical results in two vastly different mouse models of Alzheimer disease,” Dr. Galvan added, in reference to the February JCB paper, “provides robust evidence that rapamycin treatment is effective and is acting by changing a basic pathogenic process of Alzheimer that is common to both mouse models. This suggests that it may be an effective treatment for Alzheimer in humans, who also have very diverse genetic makeup and life histories.”



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