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Neuronal 'traffic jam' marks early Alzheimer's disease

nection between the transport deficit and plaque deposition.

"So, our hypothesis is that in familial Alzheimer's disease -- or in disorders such as Down syndrome where beta-APP is overexpressed -- those defects cause early failure in cellular transport," he said. "And those failures then stimulate further production of A-beta peptide, which may further poison the machinery."

Goldstein theorized that Alzheimer's disease might develop spontaneously in people without an overt genetic defect, as the transport machinery in their neurons breaks down with age. "A person could have a predisposition to the disease, or it could just be that as time progresses, one person could by chance accumulate these blockages more than another," said Goldstein. "And randomly, some people would accumulate more than others, enough to cross a critical threshold and tip the scale toward disease."

Goldstein emphasized that any application of these findings to potential diagnostic tests or new therapies remains speculative at this time. "However, if tracers could be developed that would reflect transport function, there could be imaging methods that might be helpful for diagnosis," he said. "And, if these findings continue to hold for humans, the transport machinery could be a target for drugs to preserve that machinery."

The researchers plan to continue their exploration of the transport machinery's involvement in Alzheimer's pathology by using human embryonic stem cells to differentiate into neurons in culture. Their goal is to alter those neurons genetically by introducing mutations know to cause Alzheimer's disease in people, to then test for transport defects, and then study whether those defects produce pathology similar to that seen in Alzheimer's. One of the questions they will also ask is whether amyloid plaques poison the transport machinery. If the experiments do, indeed, confirm the predictions of the transport hypothesis, then neuronal cultures could
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Source:Howard Hughes Medical Institute


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