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

Though the roles of the Aβ peptide and AβPP in the pathology of Alzheimer's disease have been well studied, many questions remain to be answered, not least being cause and effect-are plaques the root or the result of the problem? Most Down's syndrome (DS) patients eventually develop AD-like neurological damage. Their extra copy of chromosome 21, which harbors the AβPP gene, suggests that simple overexpression of AβPP may be sufficient to drive formation of amyloid plaques and cause the disease. But as Harvard Medical School's Bruce Yankner and colleagues describe in yesterday's Neuron, things are not so simple.

For starters, first author Jorge Busciglio et al. found that in cultured DS astrocytes, the activity of the non-amyloidogenic α-secretase was markedly reduced, whereas activity of β-secretase, which is involved in producing the toxic and fibrillogenic Aβ, was increased. Furthermore, though the total amount of AβPP was higher in DS cells, the amount of secreted Aβ and AβPP were much lower than normal. Aβ42, the most fibrillogenic form, occurred around the astrocytes' nucleus. The latter finding (see also Gouras et al., 2000) supports the controversial hypothesis that intracellular Aβ deposition may play a critical role in disease progression. Indeed, Busciglio et al.'s observation of intracellular Aβ42 in cortical neurons of a Down's patient who had neither (extracellular) amyloid plaques nor neurofibrillary tangles, lends credence to this hypothesis.

So what is the role of secreted amyloid proteins? Busciglio et al. found that adding recombinant AβPP to the medium of cultured DS neurons had a dramatic effect on cell viability-threefold more cells survived in its presence. Adding conditioned medium from normal astrocyte cultures to DS neurons had the same effect. Thus the primary role of the amyloid proteins may lie in protecting neurons from stress.

The localization of amyloid is not the end of the story for Down's patients. The authors noted that the changes in AβPP metabolism were reminiscent of those caused by energy depletion in COS cells. They show that adding an electron transport chain uncoupler to normal astrocytes resulted in cytoplasmic Aβ aggregation, thus linking oxidative phosphorylation with pathological changes associated with AD. Mitochondria may supply a key redox reactant, such as hydrogen peroxide, according to a preview in the March Developmental Cell by Mark Smith and colleagues at Case Western Reserve University. H2O2, they say, "can react with redox-active iron, which is associated with vulnerable neurons in AD, via the Fenton reaction, to produce the potent reactive oxygen species OH." Chelation therapies may, therefore, be promising therapeutics (see related news item).

Down Regulation
In a more general analysis of Down's syndrome, Sabine Bahn, Babraham Institute, Cambridge, UK, and colleagues from the Waisman Center Stem Cell Research Program, University of Wisconsin, used differential display to identify genes that may be up-, or downregulated in neurospheres derived from DS fetal neuronal stem cells. Published in the January 26 Lancet, their work shows that expression of several genes, including the neuron-specific transcription factor SCG10 and the cell-adhesion molecule L1, was completely repressed, while others were enhanced,or partially repressed, for example the Down's syndrome cell-adhesion molecule (DSCAM). A common factor among several of the downregulated genes was that they fall under the control of the neuron-restrictive silencer factor (REST).

REST and its targets may therefore play a key role in brain development, and may also be factors in the pathology of neurodegenerative disease in non-Down patients. Expression of SCG10, for example, has been shown to be lowered in tissue from AD brain (Okazaki et al., 1995).—Tom Fagan

Comments

  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.

    References:

    Bahn S, Mimmack M, Ryan M, Caldwell MA, Jauniaux E, Starkey M, Svendsen CN, Emson P. 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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References

News Citations

  1. Two Ways to Attack Amyloid: Metal Chelator and Antibody

Paper Citations

  1. Gouras GK, Tsai J, Naslund J, Vincent B, Edgar M, Checler F, Greenfield JP, Haroutunian V, Buxbaum JD, Xu H, Greengard P, Relkin NR. Intraneuronal Abeta42 accumulation in human brain. Am J Pathol. 2000 Jan;156(1):15-20. PubMed.
  2. Okazaki T, Wang H, Masliah E, Cao M, Johnson SA, Sundsmo M, Saitoh T, Mori N. SCG10, a neuron-specific growth-associated protein in Alzheimer's disease. Neurobiol Aging. 1995 Nov-Dec;16(6):883-94. PubMed.

Further Reading

Papers

  1. Ogawa O, Perry G, Smith MA. The "Down's" side of mitochondria. Dev Cell. 2002 Mar;2(3):255-6. PubMed.

Primary Papers

  1. Busciglio J, Pelsman A, Wong C, Pigino G, Yuan M, Mori H, Yankner BA. 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.
  2. Bahn S, Mimmack M, Ryan M, Caldwell MA, Jauniaux E, Starkey M, Svendsen CN, Emson P. 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.

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