Expression of CAP37, a Novel Inflammatory Mediator, in Alzheimer's Disease

Abstract

Recent evidence suggests that inflammation in the central nervous system plays an important role in the pathogenesis of Alzheimer's disease. However, the identity of the inflammatory mediators, cytokines, and reactive oxygen species, that orchestrate cell death and plaque biogenesis in Alzheimer's disease, have yet to be elucidated. We have identified a novel inflammatory mediator, CAP37 (Cationic Antimicrobial Protein Mi 37 kDa), that promotes mononuclear cell chemotaxis, adhesion of monocytes to endothelium, and release of oxygen radicals from monocytes. In the present immunocytochemical study, we demonstrate the expression of CAP37 in the cerebral microvasculature in Alzheimer's disease. CAP37 was not detected in brain vessels of normal controls or patients with other neuropathologic conditions such as Pick's, Parkinson's, Binswanger's disease, Progressive Supranuclear Palsy, and Candida infection. Treatment of cerebral endothelial cultures with inflammatory mediators, cytokines or beta-amyloid results in the induction of CAP37 expression. These in vitro data showing endothelial-CAP37 expression after beta-amyloid treatment together with the previous demonstration that CAP37 stimulates mononuclear cell migration and activation, suggest that CAP37 could contribute to neuronal injury in Alzheimer's disease.

Activation of microglia: A neuroinflammatory role for CAP37

“…Importantly, we have also localized CAP37 to cells of the CNS (Pereira et al, 1996b). It is present in the endothelium of the cerebral microvasculature in patients dying from Alzheimer's disease (Pereira et al, 1996b) but not in age-matched controls.…”

“…What remains equivocal is the elucidation of the underlying mechanisms and the identity of the mediators involved in initiating or regulating these processes (Goldbager et al, 1989;Breitner, 1996;Beard et al, 1998;Pasinetti, 1998;Pitchumoni and Doraiswamy, 1998;Popovic et al, 1998;Schubert et al, 1998;Yermakova et al, 1999;Cole and Ard, 2000). Recently, we localized CAP37 to the cerebral microvasculature of patients with Alzheimer's disease (Pereira et al, 1996b). What role the inflammatory mediator CAP37 serves in the CNS remains unclear.…”

“…We knew from previous work in our laboratory that human CAP37 is effective cross-species (Pereira et al, 1990a(Pereira et al, , 1990b(Pereira et al, , 1996a(Pereira et al, , 1996b. Therefore, the use of a well-characterized microglial cell line such as the mouse N9 cell line was a logical choice.…”

“…It is present in the endothelium of the cerebral microvasculature in patients dying from Alzheimer's disease (Pereira et al, 1996b) but not in age-matched controls. In vitro studies indicated that CAP37 could be induced in cerebral microvessel endothelial cells in a time-and dose-depen-dent fashion by treatment with injurious mediators such as ␤-amyloid and Escherichia coli lipopolysaccharide (LPS) and the proinflammatory cytokines tumor necrosis factor-␣ (TNF-␣) and interleukin-1␤ (IL-1␤) (Pereira et al, 1996b).…”

Neutrophil-derived azurocidin alarms the immune system

“…1A). The clinical relevance of such a mechanism is suggested by the detection of azurocidin on the EC surface of acutely inflamed appendicitis specimens (unpublished observations) and of specimens from chronic inflammatory diseases such as Morbus Alzheimer [29] and atherosclerotic plaques [30].…”