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From Here to There: AβPP as an Axonal Transport Receptor—How Could This Explain Neurodegeneration in AD?
Larry Goldstein led this live discussion on 15 July 2002. Readers are invited to submit additional comments by using our Comments form at the bottom of the page. See a follow-up live discussion background text: Axonal Transport Hypothesis Moves On to Implicate Presenilin prepared by Jorge Busciglio and Scott Brady.  View Transcript of Live Discussion — Posted 28 August 2006
Background Text
By Larry Goldstein
In neurons, most synthesis and modification of proteins, synthesis of membranes, and biogenesis of organelles occurs in the cell body. Thus, large quantities of material must be moved by the axonal transport machinery to supply the axon and the axonal terminus. Dendrites face analogous logistical problems. Retrograde neurotrophic and damage signals must also be transported over long distances to keep the cell body informed about distant events. In the case of mammalian CNS neurons, it is likely that as an important consequence of their extensive connectivity and complexity their axons, and perhaps dendrites, are very long, branched, and of diminished caliber in their distal regions. These features may predispose axonal and dendritic processes to blockage of transport when vesicles aggregate or become damaged. This would be analogous to what we and others have observed in molecular motor and other mutations that disrupt axonal transport in Drosophila.
These observations prompted us to explore potential connections between molecular motor proteins such as kinesins, which generate the forces needed for movement in axons and dendrites, and proteins and vesicles implicated in neurodegeneration, such as AβPP, which plays a key role in the development of Alzheimer's disease.
Recent work in my laboratory has led us propose the following ideas:
1) Anterograde axonal transport of a vesicle population containing BACE, presenilin, the trk receptor, and GAP-43 may require a direct interaction of AβPP and the kinesin light chain subunit of the kinesin-I molecular motor protein.
This proposal is based on several recent observations:
a) Kinesin light chain and AβPP exhibit a high-affinity biochemical interaction;
b) Kinesin light chain is required for normal transport of AβPP in mouse sciatic nerve axons;
c) Deletion of the AβPP homologue, APPL, in Drosophila causes axonal transport defects characterized by vesicle accumulations (clogs) similar to those found in kinesin-I and known axonal transport mutants;
d) Axonal content and transport of kinesin-I, BACE, presenilin, GAP-43, and the trk receptor are diminished in AbPP deletion mutants in the mouse PNS;
e) A vesicle population lacking ER markers but containing kinesin-I, BACE, presenilin, GAP-43, and the trk receptor can be inferred from immuno-isolation experiments using material from sciatic nerve and CNS axons. (Kamal et al., 2000; Gunawardena and Goldstein, 2001; Kamal et al., 2001)
2) Blockage of transport and/or axonal damage leads to increased AβPP proteolysis and Aβ production in an axonal vesicle compartment.
We observed that low levels of Aβ are normally present in axonal vesicles containing AβPP, presenilin, and BACE. We also found that AβPP proteolysis can be induced in the axon by nerve ligation in vivo or in axonal vesicles in vitro. This AβPP proteolysis gives rise to Aβ (confirmed by SELDI mass-spectrometry), a protein fragment with properties characteristic of a free cytoplasmic C-terminus of AβPP, and it causes kinesin-I to let go of the vesicles (Kamal et al., 2001).
3) Disruption of axonal transport in the presence of the Aβ region of AbβPP can cause neuronal apoptosis.
This conclusion is based on recent observations in Drosophila (Gunawardena and Goldstein, 2001):
a) Overexpression of APPL and AβPP in Drosophila neurons causes axonal vesicle accumulations;
b) Formation of axonal clogs and axonal transport of AβPP and APPL require the cytoplasmic C-terminus that contains the proposed kinesin-I binding domain;
c) Overexpression of AβPP, but not APPL, induces neuronal apoptosis. Induction of apoptosis appears to require the presence of the Aβ domain and the formation of axonal clogs mediated by the cytoplasmic C-terminus of AβPP.
d) AβPP-induced axonal blockages and neuronal apoptosis are coordinately enhanced by a 50 percent reduction in kinesin-I dosage but suppressed by a 50 percent reduction in cytoplasmic dynein dosage. We interpretate this to mean that overexpression of a motor receptor protein, such as AβPP, titrates kinesin-I motor function away from other critical cargoes in narrow caliber axons. This wold lead to transport dysfunction, clogging, and apoptosis if an Aβ region is present.
See related ARF news stories
Dynamitin in Motor Neurons: Dynamite for ALS Research?
Tau Accused of Blocking Transport, Causing APP to Linger and Nerve Processes to Wither
Suspects for Aβ Generation Spotted Together, En Route to Nerve Terminal
Axonal Transport Suggested as Function for APP
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