. Altered metabolism of the amyloid beta precursor protein is associated with mitochondrial dysfunction in Down's syndrome. Neuron. 2002 Feb 28;33(5):677-88. PubMed.


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  1. One problem in the Bahn et al. paper is that it lacks confirmation that these changes occur with real Down's syndrome cells, like primary neurons or astrocytes in culture, or in the Down's brain. When they looked at the expression of the AβPP gene, they found that that was also reduced in their Down's syndrome cells, which nobody has seen. There may be some artifact of the cell isolation that has led to amplification of a particular cell type into neurospheres.


    . Neuronal target genes of the neuron-restrictive silencer factor in neurospheres derived from fetuses with Down's syndrome: a gene expression study. Lancet. 2002 Jan 26;359(9303):310-5. PubMed.

    View all comments by Bruce Yankner
  2. This study shows very similar results to what we reported at the last Neuroscience meeting in San Diego. We found that secreted-type AβPP dose-dependently increased glial differentiation of normal human neural stem cells, and that transfection of the wildtype AβPP gene almost eliminated
    neuronal differentiation. Bahn et al. found extremely high levels of glial differentiation in the neural stem cells isolated from Down's syndrome patients, which may have an overdose of AβPP because of chromosome 21 trisomy. However, these authors found that AβPP expression was slightly decreased in the neurospheroid (undifferentiated neural stem cells). They also found reduced expression of REST, and REST regulated genes that highly
    relate to neuronal plasticity.

    This finding may contribute to the
    reduction of neurite length and abnormal morphology of neurally
    differentiated stem cells. Since Down’s patients have high AβPP expression, and REST does not directly regulate AβPP expression, both mechanisms of glial differentiation and suppression of AβPP gene expression in the Down's syndrome patient’s stem cells may need more investigation. If AβPP promotes glial differentiation of neural stem cells, it may explain in part why Down's syndrome patients develop AD-like pathology by age 30-40 years.

    View all comments by Kiminobu Sugaya

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This paper appears in the following:


  1. Down and In—the Location of Amyloid-β Does Matter