. Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease. Science. 2005 Feb 25;307(5713):1282-8. PubMed.


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  1. Building on their earlier provocative findings linking APP function to fast axonal transport, Stokin and colleagues, in this latest report, reinforce several important themes that are emerging from recent studies. First, significant neuronal pathobiology, especially evidence of altered vesicular trafficking, can be detected very early in Alzheimer disease (AD), before classical Alzheimer neuropathology appears. Second, these early disturbances at least partly stem from a behavior of APP or one of its processed forms; however, the issue of whether Aβ generation is an effect rather than the cause of this pathophysiology needs to be considered seriously. Finally, beyond its implications for Aβ generation, the defective vesicular transport observed in this study, and early endosomal-lysosomal dysfunction seen in other studies, are in their own right very likely to impair synapse function and axon/dendrite maintenance (Nixon, 2005). The new studies by the Goldstein group will hopefully encourage further exploration of these research themes, which are relatively understudied.

    The report provides evidence for an early failure of anterograde axonal transport in AD and implicates the transport motor, kinesin-1, as one route to this failure. This could nicely explain an initial report suggesting that KLC1 polymorphisms may influence risk for AD. A more generalized defect of vesicular transport in AD could also be envisioned. A dysfunctional microtubule "track," possibly involving tau, or an altered vesicular cargo, perhaps involving post-translationally modified APP, would be expected to impair not only anterograde axonal transport, but also retrograde traffic in dendrites, where dystrophy and accumulation of vesicular cargoes is more profoundly affected than in axons. The accumulating vesicles in dystrophic neurites in the Alzheimer brain include many of lysosomal origin, as initially pointed out by Robert Terry and colleagues. At the same time, many, if not most, correspond to autophagic vacuoles, which are early and late compartments of macroautophagy, a pathway for the turnover of organelles and long-lived proteins (Nixon et al. 2005). Interestingly, autophagic vacuoles are enriched in γ-secretase activity and contain Aβ in addition to the necessary components to generate Aβ (Yu et al., 2004). In the Stokin et al. study, a proportion of the vesicles accumulating in pathologic axons of the mouse model appear to have the distinctive double limiting-membrane morphology of early autophagic vacuoles, suggesting one possible source for the extra Aβ in these mice. Endosomes, another site of amyloidogenic APP processing, are known to be abundant anterograde vesicular cargoes in axons, so it will be interesting in future studies to sort out the relative contributions of these different vesicular compartments to the Aβ effect.

    See also:

    ARF related conference report


    . Endosome function and dysfunction in Alzheimer's disease and other neurodegenerative diseases. Neurobiol Aging. 2005 Mar;26(3):373-82. PubMed.

    . Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol. 2005 Feb;64(2):113-22. PubMed.

    . Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: implications for beta-amyloid peptide over-production and localization in Alzheimer's disease. Int J Biochem Cell Biol. 2004 Dec;36(12):2531-40. PubMed.

    View all comments by Ralph Nixon
  2. The paper by Stokin et al is most remarkable and very convincing. Reducing axonal transport enhanced axonopathy, increased intracellular Aβ levels and extracellular deposition. Stimulation of APP cleavage may be the consequence of enhanced presence of APP-containing vesicles in axonal and/or somatodendritic compartments due to mistrafficking. Increased intraneuronal Aβ accumulation as a consequence has been earlier shown to trigger neuronal death in APP/PS1 mouse models. Impaired axonal transport may be the result of age-dependent processes leading to axonal deafferentiation and loss of synaptic contacts.

    In my opinion, this is a milestone paper, because it shows that intraneuronal deficits, like axonopathy, are observed prior to plaque induction. It provides further evidence for a central role of intraneuronal Aβ accumulation in the pathological processes of Alzheimer disease.

    View all comments by Thomas Bayer
  3. This paper by Stokin et al. from the lab of Larry Goldstein has some interesting and important findings. I think the finding that APPsw transgenics having half the dose of kinesin-1 have increased Aβ deposition and pathology strongly argues that normal axonal transport is involved in the development of Aβ-related pathologies in AD. This is important, as it suggests that augmentation of this function or factors that prevent axonopathy may be protective against AD.

    The finding that there are neuritic swellings in very young APP transgenic mice is interesting, but whether this is relevant to AD is unclear. First, these swellings are smaller and different in appearance than the neuritic dystrophy around amyloid deposits. Second, and more importantly, the APP transgenic mice being studied overexpress mutant APP many-fold. Humans with AD of any type do not overexpress mutant APP (except in Down syndrome, in which there is APP overexpression but at a much lower level than in these mice). The overexpression of human APP increases human Aβ (required for Aβ aggregation in mice), but also may be resulting in other biological effects of mutant APP overexpression.

    It is possible that the neuritic changes described in the young APPsw mice are secondary to increased soluble Aβ. It is also possible that they are due to APPsw overexpression. Appropriate controls to sort this out might be overexpression of APPsw with the Aβ region changed in sequence or determining whether pharmacological or other inhibition of Aβ blocks the early neuritic changes. While the neuritic swellings seen in young APPsw mice are interesting and may have relevance to AD, I think this remains unclear at this point.

    View all comments by David Holtzman
  4. Kinesin molecular motor protein is involved axonal transport along microtubules. Tau protein is a major constituent of mircrotubules and thus disruption of tau (hyperphophorylation as an example) or any other part of microtubules have been shown to interfere with anterograde transport and retrograde transport. In the case of AD the research seems to point more towards APP buildup as a result of neuronal structure degradation. A drastic reduction of kinesin is merely a symptom and not directly causal of APP and amyloid beta. Presenilin mutations that affect the enzyme's activity in cutting APP are shown in a wide variety of axonal dysfucntion in AD patients.

    View all comments by Jacob Mack
  5. More support for what might be called the axonal "traffic jam" hypothesis for the pathogenesis of AD - from Larry Goldstein's lab. This paper should be read in conjunction with Orly Lazarov et al., J Neurosci March 2, 2005, which integrates work from Sam Sisodia's lab and five other labs and which provides evidence against that hypothesis. It would be nice if experiments could sharply differentiate between axonal transport peripherally and centrally. One would expect fierce traffic jams in peripheral axons, but AD patients do not appear to be particularly susceptible to peripheral neuropathy. (Peripheral neuropathy is very common in older people and is a sadly neglected research topic.)

  6. This interesting paper shows that our perception of AD physiopathology is getting more complex, but more realistic. We are far away from the simple explanation of the amyloid cascade hypothesis (ACH). To summarize, neurodegeneration is associated with a defect of the axonal transport: key players involved are the microtubules stabilized by tau proteins, the motor proteins that transport the cargo- vesicle along microtubules, and especially kinesin-I, and APP as well as PS1 in the cargo-vesicles.

    One big surprise is that the axonal transport defect generated by reducing the genetic dosage of kinesin increases Ab42 secretion and deposition. This sequence of events is the opposite of the ACH.

    To conclude, kinesin-I is likely to be an additional risk factor of AD. But behind the paper, even if bypassed, is the role of tau to stabilize and control axonal transport. Cause and effects have still to be untangled in AD.

    Among the references related to this approach, I recommend also the papers of Beyreuther on the fast axonal transport of APP and those of the Mandelkow's related to kinesin, tau, APP and the axonal transport (J Cell Biol. 2002 Mar 18;156(6):1051-63 and other related papers)

  7. Aluminum could be a co-factor in the findings of Stokin and collegues. Aluminum was found to inhibit neurofilament assembly, cytoskeletal incorporation, and axonal transport by Shea et al, 1997. Deloncle et al, 2001 found that aluminum L-glutamate causes massive mitochondrial swelling in the hippocampus of younger laboratory rats that mimics similar effects of the aging process in older animals. Stokin et al. found mitochondria in the axons. Aluminum is known to interfere with ATP and is linked with neurofibrillary degeneration. Bioaccumulation of aluminum in the human brain over the lifespan exposes the aging brain to potentially significant dosages.


    . Aluminum inhibits neurofilament assembly, cytoskeletal incorporation, and axonal transport. Dynamic nature of aluminum-induced perikaryal neurofilament accumulations as revealed by subunit turnover. Mol Chem Neuropathol. 1997 Sep-Dec;32(1-3):17-39. PubMed.

    . Ultrastructural study of rat hippocampus after chronic administration of aluminum L-glutamate: an acceleration of the aging process. Exp Gerontol. 2001 Feb;36(2):231-44. PubMed.

    View all comments by Erik Jansson
  8. This excellent study clearly demonstrates that axonal damage occurs long
    before amyloid deposition in both early stage AD and an APP mouse model.
    Furthermore, the authors demonstrate that reduced expression of the motor
    protein KCL-1 increases both the production and deposition of Aβ. However,
    it is unclear which comes first, the generation of soluble toxic Aβ
    species and then disruption of axonal transport, or disruption of
    transport leading to increased Aβ production and subsequent generation of
    toxic assemblies. A clear understanding of the pathogenic sequence is
    essential for the rational development of therapies and thus the temporal
    relationship between axonopathy and soluble Aβ species demands further
    investigation. Specifically, in light of the finding that anti-Aβ
    antibodies can lead to the clearance of early hyperphosphorylated forms of
    tau, it would be worthwhile determining if either passive or active
    immunization can rescue the pre-amyloid axonopathy.

    View all comments by Dominic Walsh

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