McPhie DL, Coopersmith R, Hines-Peralta A, Chen Y, Ivins KJ, Manly SP, Kozlowski MR, Neve KA, Neve RL. DNA synthesis and neuronal apoptosis caused by familial Alzheimer disease mutants of the amyloid precursor protein are mediated by the p21 activated kinase PAK3. J Neurosci. 2003 Jul 30;23(17):6914-27. PubMed.

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  1. McPhie et al. have done a beautiful job unraveling the signaling pathway linking FAD mutants of APP and neuronal apoptosis. Their evidence that reentry into the cell cycle is an obligatory step in this APP-induced apoptotic cascade is compelling. I'm intrigued by some similarities between the APP-driven mechanism described by McPhie and colleagues and what is seen in Niemann-Pick Type C disease:

    Mutations of both the APP gene and the NPC1 gene in humans lead to activation of similar cell cycle markers, cytoskeletal pathology with neurofibrillary tangle formation, and widespread neurodegeneration.

    Both proteins localize to transport vesicles and Rab-specific endosomal compartments. (Accumulation of b-amyloid in late endosomes has been described in NPC1 cells and in older NPC patients).

    Therefore, I wonder if there is a critical link between the function of the endosome or transport vesicles and cell cycle regulation in postmitotic neurons; in other words, if neurons exit the cell cycle to become highly specialized communicative cells, they might simply revert to cell cycling ("dedifferentiate") when this specialized function is compromised.

    Dysregulation of the neuronal trafficking process may be a key event leading to cytoskeletal pathology and neuronal death. The latter is certainly not a new idea (Sheetz et al., 1998; Kamal, 2000; Morfini et al., 2002; ARF related news story); and many more), but it may also explain a variety of disease outcomes arising from more specific or localized defects in trafficking. For instance, depending on which subset of vesicles, the type of cargo being transported, and which trafficking "arteriole" is affected, different sets of proteins/lipids may accumulate and aggregate forming different types of cytoskeletal lesions.

    References:

    Sheetz MP, Pfister KK, Bulinski JC, Cotman CW. Mechanisms of trafficking in axons and dendrites: implications for development and neurodegeneration. Prog Neurobiol. 1998 Aug;55(6):577-94. PubMed.

    Kamal A, Goldstein LS. Connecting vesicle transport to the cytoskeleton. Curr Opin Cell Biol. 2000 Aug;12(4):503-8. PubMed.

    Morfini G, Pigino G, Beffert U, Busciglio J, Brady ST. Fast axonal transport misregulation and Alzheimer's disease. Neuromolecular Med. 2002;2(2):89-99. PubMed.

    View all comments by Inez Vincent

  2. We have made an antibody to an orphan GPCR that stains very strongly human neurons with NFT and human platelets. Anybody interested in collaborating?
    Mariano Alvira, MD
    marianoa@lsbio.com
    206-374-1180

    View all comments by Mariano Alvira

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  1. Linking APP with Cell Cycle Reentry and Apoptosis—One Kinase Does the Trick

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  1. Cell Cycle Hypothesis Pedaling into Mainstream Acceptance? Results in Fly, Mouse Models Warrant a Second Look