Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila.
We tested the hypothesis that amyloid precursor protein (APP) and its relatives function as vesicular receptor proteins for kinesin-I. Deletion of the Drosophila APP-like gene (Appl) or overexpression of human APP695 or APPL constructs caused axonal transport phenotypes similar to kinesin and dynein mutants. Genetic reduction of kinesin-I expression enhanced while genetic reduction of dynein expression suppressed these phenotypes. Deletion of the C terminus of APP695 or APPL, including the kinesin binding region, disrupted axonal transport of APP695 and APPL and abolished the organelle accumulation phenotype. Neuronal apoptosis was induced only by overexpression of constructs containing both the C-terminal and Abeta regions of APP695. We discuss the possibility that axonal transport disruption may play a role in the neurodegenerative pathology of Alzheimer's disease.
Gunawardena
S
S
Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0683, USA.
Goldstein
L S
LS
D016564:Amyloid beta-Protein Precursor / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D001370:Axonal Transport / Q000235:genetics*; D016923:Cell Death / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D004330:Drosophila / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D016547:Kinesins / Q000096:biosynthesis / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism*
C489697:APLP1 protein, human; D016564:Amyloid beta-Protein Precursor; D016547:Kinesins