LOS ANGELES, Feb. 24 (Xinhua) -- Early Alzheimer's disease may be precipitated by a "traffic jam" within neurons that causes swelling and prevents proper transport of proteins and structures in the cells, researchers at the University of California, San Diego (UCSD), reported Thursday.

    This study will be published in the February 25, 2005 issue of the journal Science. The research team led by Lawrence Goldstein said their findings could provide information that might be used to develop drugs to preserve the molecular transport system and thus the viability of brain cells otherwise lost in Alzheimer's. The findings also could ultimately lead to distinctive markers of early Alzheimer's disease to be used in early diagnose.

    In mouse models of Alzheimer's disease and in human brain samples from people with the disease, researchers observed a characteristic breakdown in neurons that appears to prevent the normal movement of critical proteins to the communications centersof the nerve cells. In a vicious cycle, the traffic jam also couldincrease production of an abnormal protein that clogs neurons, leading to their failure and eventual death.

    According to Goldstein, there has been evidence that late-stage Alzheimer's disease involves a failure of the machinery that transports proteins within neurons. In studies with fruit flies, Goldstein and others had observed that over expression of the gene for a key protein that underlies Alzheimer's pathology, called beta amyloid precursor protein (beta-APP), triggers defects in axonal transport. A defective version of beta-APP is cleaved to form an aberrant form of amyloid beta (A-beta) peptide that makes up the plaques that surround the neurons of people with Alzheimer's disease.

    With the findings from fruit flies as a guide, the researchers 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. They used mice that had been engineered to have an abnormal production of human A-betapeptide that produced Alzheimer's-like plaques and subsequent neural degeneration.

    The scientists' analyses of the neurons in those mice revealed clear defects, said Goldstein. 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.

    The researchers 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. They 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," Goldstein said. "Thismakes it clear there is some mechanistic connection between the transport deficit and plaque deposition."

    The researchers hypothesized that in familial Alzheimer's disease those defects cause early failure in cellular transport, 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. But he emphasized that any application of these findings to potential diagnostic tests or new therapies remains speculative at this time.

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