Alzheimer's disease (AD), a progressive
neurodegenerative disease characterized by the accumulation of
amyloid-beta protein and neuronal loss, is the leading cause of age-related
dementia in the world today. The disease is also associated with
neuroinflammation, robust activation of astrocytes and microglia, and evidence of activation of the
complement system, localized with both fibrillar
amyloid-beta (fAbeta) plaques and tangles. The observations are consistent with a
complement-dependent component of AD progression. We have previously shown that inhibition of the major
complement receptor for C5a (CD88) with the antagonist
PMX205 results in a significant reduction in pathology in two mouse models of AD. To further characterize the role of
complement in AD-related
neuroinflammation, we examined the age- and disease-associated expression of CD88 in brain of transgenic mouse models of AD and the influence of
PMX205 on the presence of various complement activation products using flow cytometry, western blot, and immunohistochemistry. CD88 was found to be up-regulated in microglia, in the immediate vicinity of
amyloid plaques. While
thioflavine plaque load and glial recruitment is significantly reduced
after treatment with
PMX205, C1q remains co-localized with fAbeta plaques and C3 is still expressed by the recruited astrocytes. Thus, with
PMX205, potentially beneficial activities of these early
complement components may remain intact, while detrimental activities resulting from C5a-CD88 interaction are inhibited. This further supports the targeted inhibition of specific
complement mediated activities as an approach for AD
therapy.