A study in yesterday's Neuron suggests that Alzheimer's disease might be linked to a disruption of protein transport machinery in neurons. Shermali Gunawardena and Lawrence Goldstein at UC San Diego provide evidence to support the notion that AβPP functions as a receptor for vesicles that are carried along axons.

The flow of cellular traffic is especially important to maintain in axons because of the long distances they span. Organelles, vesicles laden with proteins, and other cargo migrate between the cell body and the synapse with help from motor proteins like kinesins.

The researchers found that removal of a homologue of the AβPP gene, or overexpression of AβPP in Drosophila, causes traffic jams of organelles along the narrow axons. This follows previous, biochemical work demonstrating an interaction between APP and kinesin-1. Gunawardena et al. also found that AβPP expression induced cell death in neurons, but this phenotype could be reversed by reduction of dynein, a motor protein that works in the opposite direction as kinesin, suggesting that a reduction in oncoming traffic could help move stalled cargo.

"We would argue that an important part of the development of Alzheimer's pathology may be via an effect on the neuronal transport system," Goldstein said. The hypothesis would help link the pathology of the disease to a normal function of APP, which remains elusive despite the protein's ubiquity.

The paper offers "a very interesting story for the function of APP," said Kenneth Kosik at Brigham and Women's Hospital in Boston. Kosik, who already proposed part of the current hypothesis in 1993, (Fereirra A, et al.), noted that it will be a challenge to reconcile the several diverse functions that have been proposed for APP and its related proteins.—Courtney Humphries

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Papers

  1. . Intraneuronal compartments of the amyloid precursor protein. J Neurosci. 1993 Jul;13(7):3112-23. PubMed.

Primary Papers

  1. . Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila. Neuron. 2001 Nov 8;32(3):389-401. PubMed.