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Sci. Aging Knowl. Environ., 31 July 2002
Vol. 2002, Issue 30, p. nw106
[DOI: 10.1126/sageke.2002.30.nw106]


Knot the Whole Story

Study snags new source of plaque ingredient

Mitch Leslie;2002/30/nw106

Key Words: A{beta}42 • presenilin • {gamma}-secretase

Abstract: Already snarled, the story of Alzheimer's plaques just acquired another twist. Scientists have uncovered a possible second production line for the gluey {beta}-amyloid protein that infests the brains of Alzheimer's patients. A host of drugs to squelch {beta} amyloid are under development, but the findings suggest that we might need a broader repertoire of compounds to thwart plaque buildup.

Brain-clogging {beta} amyloid is a snippet of an innocuous molecule called {beta}-amyloid precursor protein, or APP. Enzymes behead APP and dock its tail, liberating {beta} amyloid from its middle. An enzyme known as {gamma}-secretase makes this final cut to release {beta} amyloid. The identity of this enzyme remains uncertain, but many researchers suspect proteins called presenilins (see "Detangling Alzheimer's Disease"). After mincing APP, a cell usually ejects the {beta}-amyloid snippets, which can tangle outside the cell to form a plaque. However, some {beta} amyloid amasses inside the endoplasmic reticulum (ER), a meshwork of tiny tubes within the cell. Scientists have largely ignored this stored {beta} amyloid because they've thought it was locked away and unable to congeal into plaques.

Wilson and colleagues wanted to find out whether the same enzymes make the secreted {beta} amyloid and the stuff that's imprisoned in the ER. The team started by removing genes for the presenilins in mice. After collecting brain cells from embryonic mice lacking the genes, the researchers used a virus to insert the human APP gene. In culture, the altered cells secreted almost no {beta} amyloid, confirming that presenilins are necessary to release the protein fragment. However, {beta}-amyloid production didn't falter in the ER, which suggests that the presenilins aren't needed there. Bolstering that conclusion, when the scientists treated normal cells with drugs that inhibit {gamma}-secretase, they stopped secreting {beta} amyloid, but amounts in the ER didn't dip.

The study suggests that an unidentified enzyme or group of enzymes is cutting {beta} amyloid free inside the ER, says molecular biologist Robert Doms of the University of Pennsylvania in Philadelphia, a member of the research team. The findings are important because reports from earlier this year hint that the {beta} amyloid trapped in the ER isn't inert (see "Inside Job"). The sticky fibers can entangle, Doms says, forming noxious knots that might poison a cell. When the cell dies, the gobs escape, and they might seed a plaque.

The findings are likely to surprise Alzheimer's researchers, says neuroscientist Wilma Wasco of Harvard Medical School in Boston. "No one has considered that there might be different enzymes acting in different parts of the cell," she says. The discovery heralds possible problems for treatments under development that would thwart the release of {beta} amyloid from the cell by blocking {gamma}-secretase. Because the enzyme doesn't appear to work in the ER, the treatment might skip a crucial source of the nasty protein. Before they can untangle Alzheimer's plaques, researchers will have to tie up these loose ends.

--Mitch Leslie

C. A. Wilson, R. W. Doms, H. Zheng, V. M.-Y. Lee, Presenilins are not required for A{beta}42 production in the early secretory pathway. Nat. Neurosci., 29 July 2002 [e-pub ahead of print]. [Abstract] [Full Text]

Citation: M. Leslie, Knot the Whole Story. Science's SAGE KE (31 July 2002),;2002/30/nw106

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