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.

References:
Busciglio J, Pelsman A, Wong C, Pigino G, Yuam M, Mori H, Yanker B. Altered metabolism of the amyloid βprecursor protein is associated with mitochondrial dysfunction in Down's syndrome. Neuron 2002 February 28;(33):677-688. Abstract

Ogawa O, Perry G, Smith MA. The "Down's" side of mitochondria. Devel. Cell 2002 March;(2):255-256

Bahn S, Mimmack M, Ryan M, Caldwell MA, Jauniaux R, Starkey M, Svendsen CN, Emson P. Neuronal target genes of the neuron-restrictive silencer factor in neurospheres derived from fetuses with Down syndrome: a gene expression study. Lancet 2002 January 26;(359):310-315. Abstract