23 July 2002. Stockholm. The complement cascade is a series of consecutively activated proteases that, somewhat like the caspases, culminates in a powerful protein assembly that eventually kills any cell against which it is directed. In a presentation yesterday at the International 8th International Conference on Alzheimer’s Disease and Related Disorders in Stockholm, researchers found a role for this cascade in AD by showing that AβPP transgenic mice bred to lack a key component needed to rev up the complement exhibit widespread neurodegeneration (a feature curiously missing from most current mouse partial AD models) as well as increased amyloid plaque formation.
This is interesting for several reasons. First, it gives researchers a new handle on understanding the emerging question whether part of the inflammation widely observed in AD might be beneficial by helping to remove amyloid. Second, it may help to understand the activation process of microglia. While known to engulf and clear away plaque when properly activated, this small, quasi-immune glial cell has nevertheless proved elusive and difficult to study.
More generally, the study continues to broaden the range of functions, both good and bad, that have begun to emerge for the complement cascade in recent years. Originally discovered as part of the first line of defense against bacteria, the complement is now known to be an indispensable step in the activation of mast cells, but also to figure in the pathogenesis of the autoimmune disease lupus erythematosus, in asthma, and in reperfusion injury, a serious problem in surgical practice.
Tony Wyss-Coray at the University of California, San Francisco, and coworkers elsewhere, showed a poster that also appears in the PNAS early edition this week. The study continued previous work showing that AβPP transgenic mice that were also overproducing the proinflammatory cytokine TGF-1β had activated microglia and less Aβ accumulation than mice transgenic only for AβPP. What, however, was mediating this activation? A hint existed in that these APP/TGF-1β mice had elevated levels of C3, a central step in complement activation.
Wyss-Coray and colleagues then bred PDAPP mice with mice transgenic for the natural complement inhibitor Crry, originally made by co-author Richard Quigg at the University of Chicago. At 10 months, these mice had higher Aβ levels in neocortex and hippocampus, more plaques and altered Aβ turnover. At the same age, complement-deficient mice had 50 percent fewer neurons in the CA3 subfield of the hippocampus, which is known to degenerate early in human AD, while three-month old mice did not yet have this cell loss. Neuritic dystrophy was widespread but the microglia, meanwhile, were less activated in the AβPP/Crry mice.
The complement has previously been shown to be involved in AD. It is upregulated in AD, and aggregated Aβ can activate it in vitro. This study takes previous work in vivo.—Gabrielle Strobel