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Neuronal 'traffic jam' marks early Alzheimer's disease

Alzheimer's disease.

"With the findings from fruit flies as our guide, we decided to look at mouse models of Alzheimer's disease early in their life, before plaque formation, to see if we could detect early evidence of abnormal axonal transport," said Goldstein. The researchers used mice that had been engineered to have an abnormal production of human A-beta peptide that produced Alzheimer's-like plaques and subsequent neural degeneration.

The scientists' analyses of the neurons in those mice revealed clear defects, said Goldstein. "What we saw quite early in the life of those animals -- well before any plaque deposition -- were obvious axonal defects," said Goldstein. "We saw large swellings in their axons. And when we looked at those swellings using electron microscopy and biochemical markers, they looked just like the axonal transport blockages we saw in fruit flies." Detailed studies of the neurons revealed what Goldstein termed a "traffic jam" of transport-related proteins, organelles and sac-like vesicles that are the cargo-carriers for cellular proteins.

Goldstein and his colleagues also examined brain sections taken at autopsy from humans with different stages of Alzheimer's disease. They detected the same kinds of swelling in those samples that they had seen in the mice. "This was a small, initial neuropathological study, but we believe that it is significant," said Goldstein. "We found in the early cases a very strong, statistically meaningful swelling in the neurons."

The researchers tested whether they could enhance the pathology they observed in the mice and humans by reducing the levels of a key transport protein, kinesin-1, the cell's principal molecular motor for transporting proteins. "We made a modest reduction in the level of a motor protein called kinesin-1 in the mice, and we got a considerable increase in plaque production and plaque deposition," said Goldstein. "This makes it clear there is some mechanistic con
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Source:Howard Hughes Medical Institute


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