The double-edged flower: roles of complement protein C1q in neurodegenerative diseases

Abstract

A role for the complement cascade in AD neuropathology was hypothesized over a decade ago, and the results of a significant number of in vitro studies are consistent with the involvement of this pathway in AD pathogenesis (reviewed in). Since C1q is colocalized with thioflavine-positive plaques and the C5b-9 complement membrane attack complex is detected in AD brain at autopsy, it is reasonable to hypothesize that complement activation has a role in the manifestation of AD either by its lytic capacity or as a trigger of glial infiltration and initiation of potentially damaging inflammation. The observed diminished glial activation and reduced loss of neuronal integrity in a murine model overexpressing mutant human APP but lacking the ability to activate the classical complement cascade provide the first direct evidence for a detrimental role of C1q, and presumably activation of the classical complement pathway in an animal model of AD. Research is now focused on generating mouse models that more closely mimic the human disease, so that the role of complement activation and inflammation on the behavioral/learning and memory dysfunction that occurs in this disease can be assessed. In addition, candidate therapies such as targeted inhibition of complement activation will need to be tested in these animal models as a step toward treatment of humans with the disease. However, it is important that the potential for a protective effect of C1q early on in disease progression should not be overlooked. Rather, strategies that enhance or mimic the protective effects of C1q as well as strategies that inhibit the detrimental processes should be fully investigated.