Kinesin-mediated transport in a Drosophila model of Alzheimer's disease. S.D. Gunawardena , R. Laymon , L.S.B. Goldstein. Cell & Molec Medicine/HHMI, Univ California San Diego, La Jolla, CA.

   Alzheimer's disease (AD) is a neurodegenerative disease characterized by the accumulation of amyloid b (Ab), accompanied by neuronal death. We previously showed that both human APP and Drosophila APPL function as kinesin receptors in axonal transport. Excess APP leads to axonal clogging and neuronal death that is enhanced by reduction in kinesin and suppressed by reduction in dynein. Both the Ab and C-terminal regions are necessary for neuronal death. Since Drosophila contains presenilin and nicastrin genes implicated in g-secretase activity, perhaps neuronal death results from the aberrant cleavage of APP within blockages resulting in Ab toxicity. We find that reducing or increasing the dose of presenilin, which is associated with g-secretase activity, with excess APP leads to suppression of axonal blockages and neuronal death. Excess presenilin alone has no effect on axonal transport, but reducing the dose of kinesin with excess presenilin causes axonal blockages, but not neuronal death. Reducing the dose of dynein with excess presenilin has no effect. We suggest that excess presenilin degrades APP leading to reduced blockages while reduced presenilin may diminish the population of APP containing vesicles. We propose that presenilin may also function in kinesin-mediated transport. Elucidating the normal mechanisms of APP transport may become important not only in understanding but also in developing treatments for the pathogenesis of AD.