| Alzheimer's Disease (AD), a progressive neurodegenerative disorder characterized by amyloid-beta and hyperphosphorylated tau accumulation, and neuronal loss, is associated with aging. Genetic studies have contributed to the development of the amyloid cascade hypothesis, as a cause of disease development. An immune presence, including activated glia and complement deposition, in reaction to amyloid buildup, has produced the hypothesis that complement activation is a substantial component in AD progression.;Most AD mouse models lack substantial neuronal degeneration or loss, which could impact their learning impairment and thus their usefulness as a model for human AD. Previous experiments, demonstrated weaker mouse complement activation, in response to fibrillar Abeta (fAbeta) compared with human complement, possibly due to differences in human vs. mouse C1q A chain. It was hypothesized that weaker complement activation could result in lower neuronal loss. Thus, the A chain of mouse complement component C1q, was altered to mimic human C1q. However, increased fAbeta-C1q interaction was not observed after the modification. The subsequently published crystal structure of C1q globular head domains, suggested that a similar 3-dimensional arrangement of amino acids on the B chain subunit provides sufficient interaction between mouse C1q and fAbeta, without the A chain contribution. One complement activation product, C5a, is an initiator of inflammation. Analysis of AD model mice revealed that CNS expression of CD88, a cellular receptor for C5a, increases with age and is localized around Abeta plaques. Targeting C5a activity, with a CD88 antagonist (PMX205) for 12 weeks, resulted in a significant reduction in thoiflavine positive Abeta plaques and activated glia. Additionally, reductions in hyperphosphorylated tau (in 3xTg mice) and neuronal damage in the hippocampus (in Tg2576 mice) were observed. Reductions in pathology were correlated with improved contextual memory in Tg2576 mice. Treatment with PMX205, demonstrated that CD88 in microglia surrounding plaques was reduced in parallel with reduced plaque load. Importantly, the treatment does not negatively interfere with complement components which have been suggested to be protective in other AD models. These results suggest, inhibition of CD88 may serve as a therapy towards AD. |
