This work further confirms the importance of axonal retrograde transport in the development of neurodegeneration (at least in motor neuron degeneration). Although whether the concept applies to Alzheimer research remains to be examined, it seems worth trying.

View all comments by Takaomi Saido

This paper mixes well with the dynamitin paper that was published some time back. Also, its chaperone function is definitely interesting. The only other chaperones studied in ALS are HSP70 and CCS. However, no mutations in any chaperones have been identified before. The HSP70 knockout and the CCS knockout mice also showed no change in phenotype when crossed to the SOD1 mice.

View all comments by Tennore Ramesh

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....  Read more

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.

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

Nixon RA; Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM. Extensive Involvement of Autophagy in Alzheimer Disease: An Immuno-Electron Microscopy Study. Journal of Neuropathology and Experimental Neurology: 2005 Feb; 64(2):113-122.

Yu WH, Kumar A, Peterhoff C, Shapiro Kulkane L, Uchiyama Y, Lamb BT, Cuervo AM, Nixon RA. Autophagic vacuoles are enriched in APP-secretase activities: Implications for Aβ peptide over-production and localization in Alzheimer’s disease. International Journal of Biochemistry and Cell Biology 2004; 36:2531-2540. Abstract

See also ARF related conference report.

View all comments by Ralph Nixon

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

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...  Read more

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

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

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.

References:
T.B. Shea, E. Wheeler and C. Jung, Aluminum inhibits neurofilament assembly, cytoskeletal incorporation and axonal transport. Dynamic nature of aluminum-induced perikaryl neuro-filament accumulations as revealed by subunit turnover, Mol Chem Neuropathol 32(1-3)1997, 17-39

R. Deloncle, F. Huguet, B. Fernandez, N. Quellard, P. Babin and O. Guillard, Ultrastructural study of rat hippocampus after chronic adminstration of aluminum L-glutamate: an acceleration of the aging process, Exp Gerontol 36(2) 2001, 231-44

View all comments by Erik Jansson

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