1 March 2002. 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).
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.
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