Disruption of axonal transport and neuronal viability by amyloid precursorprotein mutations in Drosophila

We tested the hypothesis that amyloid precursor protein (APP) and its relat ives 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, disrup ted axonal transport of APP695 and APPL and abolished the organelle accumul ation phenotype. Neuronal apoptosis was induced only by overexpression of c onstructs containing both the C-terminal and A beta regions of APP695. We d iscuss the possibility that axonal transport disruption may play a role in the neurodegenerative pathology of Alzheimer's disease.