Sci. Aging Knowl. Environ., 26 June 2002
Vol. 2002, Issue 25, p. nw86
[DOI: 10.1126/sageke.2002.25.nw86]


Double Whammy: Alzheimer's protein might clog arteries (Atherosclerosis; Alzheimer's disease)

Mary Beckman;2002/25/nw86

Key Words: foam cells • {beta}-secretase • inducible NO synthase • phagocytosis • IFN-{gamma}

Abstract: Like a sleazy lawyer who moonlights as a telemarketer, a key protein in Alzheimer's disease can cause trouble in multiple ways. It kicks off the cascade that leads to clogged arteries in atherosclerosis, new research shows. The unexpected link between a dementia and heart disease might lead to better understanding of--and better treatments for--both ailments of the elderly.

In atherosclerosis, hard plaques encrust artery walls and stiffen them, leading to heart disease. These plaques are chock-full of lipids, blood cells called platelets, and a variety of immune system components--including macrophages, which chew up unwanted cells and microbial invaders. Smooth muscle cells secure plaques by capping them with the protein collagen. As the disease progresses, macrophages churn out nitric oxide, which induces smooth muscle cells to commit suicide. With no nearby collagen-producing custodians, some plaque coverings thin and rupture, spilling lipids into the bloodstream that can trigger clot formation, which in turn can clog vessels and instigate a heart attack or stroke.

Researchers have shown previously that platelets contain {beta}-amyloid precursor protein (APP), whose processed form, {beta} amyloid, amasses in Alzheimer's brain plaques (see "Detangling Alzheimer's Disease"). {beta} amyloid also shows up in atherosclerotic plaques and macrophages. The observation that macrophages, {beta} amyloid, and platelets convene in plaques inspired Guido De Meyer and colleagues to find out whether macrophages turn APP into mature {beta} amyloid.

To investigate, they incubated macrophages with platelets in culture. Using two kinds of microscopy, they showed that macrophages gobbled the platelets. This feeding frenzy stimulated the macrophages to generate nitric oxide. After engulfing platelets, macrophages contained a little precursor protein and were brimming with {beta} amyloid but unfed macrophages bore neither. The researchers then found that they could stimulate macrophages to produce nitric oxide by dribbling {beta} amyloid into the cell culture. Finally, the team found that the macrophages produce messenger RNA for an enzyme that trims {beta} amyloid from APP and that inhibiting this enzyme in culture prevents {beta} amyloid and nitric oxide production. Taken together, the data suggest that macrophages create {beta} amyloid from platelet APP, which then spawns the nitric oxide that leads to plaque deterioration.

De Meyer, a pharmacologist at the University of Antwerp, Belgium, says that additional work is required to determine whether the same phenomenon occurs in people. But if the result holds up, researchers can test whether drugs in development for Alzheimer's disease quell atherosclerosis. And the benefit might go both ways. "There are also some indications that cholesterol-lowering statins may lead to less {beta} amyloid," De Meyer says. Neuroscientist Rudolph Tanzi of Massachusetts General Hospital in Charlestown says that the work suggests a new source of {beta} amyloid that Alzheimer's researchers need to consider. "{beta} amyloid cycles from the brain to blood to the brain," he says. "We thought [that the circulating peptide] came from the brain. This work says maybe it's coming from the blood." Detailing the troublemaker's nefarious activities should help researchers who study Alzheimer's disease and atherosclerosis get to the heart of its mysteries.

--Mary Beckman; suggested by Galynn Zitnick

G. R. Y. De Meyer, D. M. M. De Cleen, S. Cooper, M. W. M. Knaapen, D. M. Jans, W. Martinet, A. G. Herman, H. Bult, M. M. Kockx, Platelet phagocytosis and processing of {beta}-amyloid precursor protein as a mechanism of macrophage activation in atherosclerosis. Circ. Res. 90, 1197-1204 (2002). [Abstract] [Full Text]

Citation: M. Beckman, Double Whammy: Alzheimer's protein might clog arteries (Atherosclerosis; Alzheimer's disease). Science's SAGE KE (26 June 2002),;2002/25/nw86

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