. Extracellular phosphorylation of the amyloid β-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer's disease. EMBO J. 2011 Jun 1;30(11):2255-65. PubMed.

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  1. The confirmation of Aβ phosphorylation in AD brains in this paper and the suggested contribution to AD pathology supports a role for phosphorylated Aβ.

    After noting that phosphorylation defects were a major pathological feature of AD, I discovered that Aβ itself could be phosphorylated, and that the phosphorylated Aβ form was significantly more toxic to neuronal cells (Milton, 2001). I suggested that Aβ becomes phosphorylated inside the neuronal cells of AD patients (Milton, 2001; Milton, 2005a). This modification causes the compound to become highly toxic, killing neurons. As a result of the neuronal damage, Aβ plaques build up around the dead cells, which is a normal response to cell death. It is possible that not all Aβ-plaques are toxic, but that pAβ plays a direct role in the formation of the toxic species, which cause further neural degeneration.

    The extracellular phosphorylation of Aβ documented here provides another source of the toxin and removes the necessity for cellular uptake prior to the phosphorylation of Aβ.

    It should be noted that the phosphorylated Aβ I detected in AD brain and NT2 neurons cross-reacted with an anti-phosphoserine antibody and an anti amyloid-β antibody (Milton, 2006). The assay would have detected Aβ phosphorylated at either Ser8 (as suggested here for PKA-mediated phosphorylation) or Ser26 (as I suggested for CDC2 mediated phosphorylation).

    I look forward to a surge in interest in phosphorylated Aβ 10 years on from my original paper.

    Please note a potential conflict of interest as I filed the now abandoned patents for phosphorylated amyloid-β derivatives (Milton, 2005b).

     References:

    See also Milton, N.G.N. (2005b) Phosphorylated amyloid-beta1-43 protein and its use in the treatment of Alzheimer's disease. European Patent Publication Number EP1538163; and Milton, N.G.N. (2006) Amyloid-beta phosphorylation. In Cell Biology Techniques, Eds D. Rickwood, J. Graham & J.R. Harris, Wiley, London pp 364-368.

    References:

    . Phosphorylation of amyloid-beta at the serine 26 residue by human cdc2 kinase. Neuroreport. 2001 Dec 4;12(17):3839-44. PubMed.

    . Phosphorylated amyloid-beta: the toxic intermediate in alzheimer's disease neurodegeneration. Subcell Biochem. 2005;38:381-402. PubMed.