Abstract
BackgroundA causal role of the complement system in Alzheimer's disease pathogenesis has been postulated based on the identification of different activated components up to the membrane attack complex at amyloid plaques in brain. However, histological studies of amyloid plaque bearing APP transgenic mice provided only evidence for an activation of the early parts of the complement cascade. To better understand the contribution of normal aging and amyloid deposition to the increase in complement activation we performed a detailed characterization of the expression of the major mouse complement components.MethodsAPP23 mice expressing human APP751 with the Swedish double mutation as well as C57BL/6 mice were used at different ages. mRNA was quantified by Realtime PCR and the age- as well as amyloid induced changes determined. The protein levels of complement C1q and C3 were analysed by Western blotting. Histology was done to test for amyloid plaque association and activation of the complement cascade.ResultsHigh mRNA levels were detected for C1q and some inhibitory complement components. The expression of most activating components starting at C3 was low. Expression of C1q, C3, C4, C5 and factor B mRNA increased with age in control C57BL/6 mice. C1q and C3 mRNA showed a substantial additional elevation during amyloid formation in APP23 mice. This increase was confirmed on the protein level using Western blotting, whereas immunohistology indicated a recruitment of complement to amyloid plaques up to the C3 convertase.ConclusionEarly but not late components of the mouse complement system show an age-dependent increase in expression. The response to amyloid deposition is comparatively smaller. The low expression of C3 and C5 and failure to upregulate C5 and downstream components differs from human AD brain and likely contributes to the lack of full complement activation in APP transgenic mice.
Highlights
A causal role of the complement system in Alzheimer's disease pathogenesis has been postulated based on the identification of different activated components up to the membrane attack complex at amyloid plaques in brain
APP23 mice overexpressing human APP751 with the Swedish double mutation [31] as well as C57BL/6 and BUB/BnJ [32] mice were analyzed at the age of 3-30 months. mRNA was quantified by Realtime PCR [33], proteins were analyzed by Western blotting and histology
Results mRNA expression of complement components in amyloid plaque-containing APP23 and control mouse brain APP23 mice show an age-related increase in amyloid plaque deposition as well as in plaque-associated alterations such as gliosis
Summary
A causal role of the complement system in Alzheimer's disease pathogenesis has been postulated based on the identification of different activated components up to the membrane attack complex at amyloid plaques in brain. The complement system is a major effector of the humoral immune system playing an important role in both innate and acquired immunogenicity [1] It consists of various proteins acting in different but merging cascades, the main ones being the classical and the alternative pathway. Histological studies of AD brain detected complement components in association with parenchymal amyloid plaques and neurofibrillary tangles [8] This includes key components for activation up to the formed membrane attack complex [915]. Histological studies of amyloid plaque bearing APP transgenic mice detected early complement components, whereas downstream components forming the membrane attack complex were missing [21]. While it has been argued that human Aβ may be a poor activator of mouse complement, humanization of the C1q A chain did not increase activation] [23,24]
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