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NEUROLOGY Cellular Energy Crisis May Link Down Syndrome, Alzheimer'sGlitch in Power-generating Mitochondria Could Upset Amyloid Processing In the general population, Alzheimer's disease strikes an unlucky few at a relatively late age, but for those with Down syndrome, the disease is more unforgiving. Most people with the syndrome develop Alzheimer's pathology by late middle age, including deposits of the plaque-forming protein amyloid-beta that are often more severe than in most other Alzheimer's patients. Why the two diseases are intimately linked is unclear. But a study led by Bruce Yankner, HMS associate professor of neurology at Children's Hospital, suggests that a malfunction in the mitochondria of Down syndrome patients may be to blame. The resulting loss in cellular energy may explain how amyloid-beta slowly clogs the brain and why Alzheimer's is a disease of aging.
Impaired mitochondria may be to blame for the early onset of Alzheimer's disease in people with Down syndrome, according to research by Bruce Yankner, Menglan Yuan (l to r), and Jorge Busciglio (inset). Photo by Steve Gilbert; inset courtesy of Jorge Busciglio A Destructive ImbalanceDown syndrome is caused by an extra copy of chromosome 21, which can lead to the overexpression of certain proteins. The amyloid precursor protein, which is cleaved to form amyloid-beta, is located on chromosome 21, and presumably its increased production contributes to the early onset of Alzheimer's. Higher expression of the precursor protein in cultured cells or transgenic mouse models, however, is not enough to create amyloid deposits. In the Feb. 28 Neuron, Jorge Busciglio, Bruce Yankner, and colleagues report that there is a change in how the amyloid protein is processed in neurons and astrocytes of the Down syndrome brain.
A Down syndrome astrocyte with the nucleus in red has diminished mitochondrial function and accumulates the pathogenic form of amyloid-beta, shown in green clumps. There are several ways to slice the amyloid precursor protein: one cut yields amyloid-beta, but a different cut yields a fragment that may have protective activity in the cell, and the two are mutually exclusive. Yankner's group found that although overall expression of the precursor protein was higher in Down syndrome neurons, the amount of the potentially protective fragment was reduced. This alter ego to amyloid-beta also was reduced in a series of Down syndrome brains. Clearly, a switch from the protective form to amyloid-beta could be dangerous to the cell. In culture, Down syndrome neurons die off relatively quickly, but the team found that a recombinant form of the protective amyloid precursor fragment could rescue this degeneration. Amyloid-beta itself comes in two sizes--the longer form is thought to be more pathogenic and toxic, and more likely to form plaques. "We found that what was accumulating in Down's syndrome cells was not the benign form, but this pathogenic form, which is the direct precursor of the senile plaques," Yankner said. The researchers found that the trafficking of the amyloid protein was also significantly altered in Down syndrome astrocytes. Normally it is quickly shuttled out of the cell once it is produced. But in Down syndrome cells, the amyloid-beta remained inside the cell, localized in the organelles of the secretory pathway through which the precursor protein is normally trafficked. Furthermore, the protein had accumulated in highly insoluble lumps; it was as if it had encountered a traffic jam on a highway where it normally breezed along. Or perhaps it had just run out of gas. The processing, trafficking, and folding of proteins is powered by ATP, which is generated in the mitochondria. Yankner's team had encountered a similar processing pattern several years ago when they disrupted mitochondrial function in cells. Using a dye that registered that function, the team found the mitochondria of Down syndrome astrocytes were significantly less energetic. "We think that the accumulation of amyloid-beta," Yankner said, "is due to abnormal protein trafficking of the amyloid precursor protein or folding of the amyloid-beta protein once it's generated in these cells, due to a loss of energy metabolism." The Disease LinkPeople with Down syndrome have a reduced life expectancy and often exhibit signs of premature aging, and Alzheimer's is most prevalent in the aging population. The current findings provide a link between mitochondrial dysfunction that normally occurs in the aging brain and the predisposition to Alzheimer's. Mitochondrial dysfunction may trigger the accumulation of amyloid-beta, which impairs neurons and eventually kills them.The researchers now are pursuing the question of what the initial trigger of mitochondrial dysfunction might be. Recent, related studies from Bruce Ames's laboratory at the University of California, Berkeley, have shown that feeding mitochondrial metabolites to aged rats could help slow the signs of age-related decay, suggesting a therapeutic angle on targeting the mitochondria in diseases of aging. --Courtney Humphries |
