A University of Colorado at Boulder study of landlocked salmon indicates they possess a genetically programmed "aging clock" timed by reproduction, which may provide insight into human aging and Alzheimer’s disease.
Richard Jones, a professor emeritus in the environmental, population and organismic biology department, said the study is the first ever to identify deposits of a peptide known as beta amyloid in the brains of an aging, wild vertebrate population under natural conditions. Sticky deposits of beta amyloid, called plaques, are considered one of the hallmarks of aging and Alzheimer’s disease in human brains.
Many neurologists believe that beta amyloid -- produced when a brain protein known as amyloid precursor protein, or APP, is chopped into pieces by enzymes -- causes brain neurons to degenerate and die, said CU-Boulder doctoral student and lead study author Tammy Maldonado. But other researchers now believe beta-amyloid deposits in the brain are relatively harmless and may even be beneficial.
The CU-Boulder biologists found that specific brain regions of spawning salmon exhibit neurodegeneration and amyloid plaques remarkably similar to those in humans. But other brain areas used for migration and spawning tasks continued to function, despite the presence of beta-amyloid plaques, Maldonado said.
Olfactory regions of the brain, for example, functioned well enough to allow the fish to return to their streams of origin and sense pheromones to coordinate spawning behavior, despite the presence of APP and amyloid plaques. Similarly, brain regions controlling magnetic and vibration senses, which are important in sexual behavior of salmon, also functioned despite build-ups of beta-amyloid deposits and APP in those areas of the brain, she said.
"Instead of being murderers, amyloid plaques may be allies of the brain during times of stress and trauma," said Jones. "Our work on salmon could indicate amyloid plaques may form around dead neurons somewhat like Band-Aids, preventing toxins produced by dead neurons from reaching healthy neurons."
A paper on the subject authored by Maldonado, Jones and CU-Boulder biology Professor David Norris is being published in the March 10 issue of Brain Research, one of the world’s premier neurological journals. Supported by the National Science Foundation and the National Institutes of Health, the research effort also included former CU-Boulder doctoral student Laura Carruth and several Colorado Division of Wildlife biologists.
For the study, the researchers used a wild population of kokanee salmon, a landlocked variety of sockeye salmon obtained from the Colorado River near Granby Reservoir in the central Colorado mountains. All salmon species indigenous to the Pacific Ocean reproduce just once – usually between 2 years and 4 years of age – and then almost immediately die.
The brains of the kokanee salmon in the study were preserved, sliced into cross-sections and chemically stained to identify areas of APP and amyloid plaque build-up. Salmon are a good model to study because the physiological cascade of aging effects proceeds much like that in humans, although salmon run an astonishingly swift course toward death following reproduction, said Norris.
Both salmon and humans exhibit remarkably similar aging symptoms, including brain decay, cardiovascular disease, muscle atrophy, skin lesions and the resorption of internal organs. Laboratory studies of APP and beta-amyloid molecules obtained from salmon brains and from a small piece of brain tissue from a human who died with Alzheimer’s disease showed the molecules "to be very similar if not identical," said Maldonado.
In the study, young, castrated kokanee salmon were shown to live to be 7 years to 9 years old, instead of dying at age 2 or 3 like normal, spawning kokanee salmon, suggesting that salmon have an "aging alarm" timed to go off at reproduction. Massive surges of a stress hormone known as cortisol occur in both reproducing and sterile salmon just prior to the onset of the rapid aging process and subsequent death, Norris said.
"Cortisol surges may help these fish metabolize sugar and produce enough energy to locate their home streams and reproduce, but the surges also eventually may trigger brain aging and death," said Maldonado. The researchers plan to inject juvenile salmon with cortisol and several other hormones next fall to see if the experiment causes amyloid plaques to form in the brains of the study fish.
Lab experiments have shown that high levels of cortisol spikes that occur in the blood of aging rats and humans, are present in higher quantities in Alzheimer victims, and are known to kill certain areas of neurons in the brain.
"If we find that stress hormones cause amyloid plaques to form in salmon brains, that would be quite a breakthrough," said Norris.
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