APP and Axonal Transport: A Report from Bar Harbor

Series - Enabling Technologies for Alzheimer Disease Research: 2005 Bar Harbor Workshop:

It is widely accepted that at least a fraction of APP is actively transported along the axon to the nerve terminal and does not return to the cell body. Current points of debate on APP and axonal transport include whether APP binds directly to the motor protein kinesin or indirectly as part of a complex with scaffolding proteins, how the transport of APP relates to its processing, and whether axonal transport deficits are an early and critical event in AD pathogenesis.

Evidence is also now emerging that APP can impair retrograde transport. For example, studies with Down syndrome models indicate that elevated levels of APP, particularly certain cleavage fragments, can disrupt the proper fusion and subsequent retrograde transport of NGF-containing vesicles (see ARF conference news). In addition to the obvious connection this makes between APP and neuronal survival, this raises the question of whether there exists a wider system of signaling endosomes in neurons that may be disrupted by APP or other proteins implicated in neurodegeneration.

Given that anterograde and retrograde axonal transport occurs along microtubules, the question arises whether this context offers a connection between the microtubule-binding protein tau and APP. In cell-culture experiments, increasing the levels of tau can disrupt transport, perhaps because tau and kinesin compete for the same binding sites on microtubules. It is not clear yet whether this happens in vivo in AD; imaging methods to probe this process in situ are a priority. (For more on a dynamic model of tau in axonal transport, see ARF conference news.)

Overall, the cause and significance of transport deficits in AD remain a topic of debate. How large a transport deficit a neuron can tolerate over time should remain a focus of active research.

—Gabrielle Strobel

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References

News Citations

  1. San Diego: Too Much APP Blocks Transport, Starves Down's Neurons
  2. Dublin: The Tao of Tau

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