Taking Complement Well

Abstract

Like the baby brother left holding the cookie jar his sister emptied, not all inflammation in Alzheimer's disease (AD) is as blameworthy as appearances suggest. According to new research, certain inflammatory molecules permeate ravaged areas of a diseased brain, but they help more than hurt, at least in mice. The results might allow investigators to determine which inflammatory processes to bolster and which to suppress in the effort to curtail AD. The hallmarks of AD are neuronal degeneration and plaques full of β amyloid, a protein formed by the aberrant processing of β-amyloid precursor protein (APP) (see "Detangling Alzheimer's Disease" ). Evidence conflicts about whether inflammation might cause one or both of these problems. It flourishes in Alzheimer's brains, and anti-inflammatory drugs appear to slow cognitive decline (see McGeer Review ). On the other hand, stimulating the process can slow plaque formation in a mouse model of the disease. Researchers aren't sure how inflammation can swing both ways, but the answer might lie in a biochemical system named the complement cascade that helps the immune system eliminate microbes and infected cells. Some proteins involved in the complement cascade, including one called C3, break down into an active form, C3b, in response to invasion. C3b marks foreign proteins on cells and attracts other complement proteins that punch holes in cell membranes they encounter. The tagging capability also targets proteins for destruction, and this skill might impede AD. The hole punchers, in contrast, perforate willy-nilly and can kill healthy cells--including neurons--in their vicinity. Human Alzheimer's plaques teem with C3b-adorned β amyloid and the cell-drilling proteins, leading some researchers to argue that β amyloid draws C3. Its product summons the piercing proteins, which then kill off nearby neurons. To pin down the complement cascade's role in AD, Wyss-Coray and colleagues thwarted the system in mice. From previous work, Wyss-Coray knew that mice engineered to manufacture human APP (hAPP) accumulate less brain β amyloid if they also overproduce TGF-β, a molecule that promotes inflammation. In the current study, they found that such mice had twice as much C3 in their brains as did hAPP mice without TGF-β. To find out if blocking C3 enhances plaque formation, the team created hAPP mice that crank out a protein called Crry, a complement inhibitor. By 1 year of age, the animals had accumulated two to three times as much brain β amyloid as had mice with complement, and they had lost almost half of their Alzheimer-susceptible neurons. These results indicate that the complement cascade protects brains from β-amyloid deposits. Mouse and human diseases differ, cautions neuroscientist Patrick McGeer of the University of British Columbia in Vancouver, so the current work might not shed light on human AD. For example, human Alzheimer's brains have far more hole punchers than the animal brains do. However, neurobiologist Joseph Rogers of the Sun Health Research Institute in Sun City, Arizona, says McGeer's reservations "don't negate the impact of the study." Whether or not the work relates to the pore-forming proteins, he says, "this study shows [that] if you don't have complement, [β amyloid] builds up. We need to learn to harness this beneficial mechanism while dampening its toxic effects." In AD as in life, sometimes it's nice to get complemented. --Mary Beckman; suggested by Amir Sadighi Akha T. Wyss-Coray, F. Yan, A. H.-T. Lin, J. D. Lambris, J. J. Alexander, R. J. Quigg, E. Masliah, Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice. Proc. Natl. Acad. Sci. U.S.A. , 15 July 2002 [e-pub ahead of print]. [Abstract] [Full text]