Abstract
BackgroundComplement proteins and activation products have been found associated with neuropathology in Alzheimer's disease (AD). Recently, a C5a receptor antagonist was shown to suppress neuropathology in two murine models of AD, Tg2576 and 3xTg. Previously, a genetic deficiency of C1q in the Tg2576 mouse model showed an accumulation of fibrillar plaques similar to the complement sufficient Tg2576, but reactive glia were significantly decreased and neuronal integrity was improved suggesting detrimental consequences for complement activation in AD. The goal of this study was to define the role of the classical complement activation pathway in the progression of pathology in the 3xTg mouse that develops tangles in addition to fibrillar plaques (more closely reflecting human AD pathology) and to assess the influence of complement in a model of AD with a higher level of complement hemolytic activity.Methods3xTg mice deficient in C1q (3xTgQ-/-) were generated, and both 3xTg and 3xTgQ-/- were backcrossed to the BUB mouse strain which has higher in vitro hemolytic complement activity. Mice were aged and perfused, and brain sections stained for pathological markers or analyzed for proinflammatory marker expression.Results3xTgQ-/- mice showed similar amounts of fibrillar amyloid, reactive glia and hyperphosphorylated tau as the C1q-sufficient 3xTg at the ages analyzed. However, 3xTg and 3xTgQ-/- on the BUB background developed pathology earlier than on the original 3xTg background, although the presence of C1q had no effect on neuropathological and pro-inflammatory markers. In contrast to that seen in other transgenic models of AD, C1q, C4 and C3 immunoreactivity was undetectable on the plaques of 3xTg in any background, although C3 was associated with reactive astrocytes surrounding the plaques. Importantly, properdin a component of the alternative complement pathway was associated with plaques in all models.ConclusionsIn contrast to previously investigated transgenic models of AD, development of neuropathology in 3xTg mice, which progresses much slower than other murine models, may not be influenced by fibrillar amyloid mediated activation of the classical complement pathway, suggesting that the alternative complement pathway activation or a C3-independent cleavage of C5 could account for the detrimental effects in these mice that are prevented by the C5a receptor antagonist. Furthermore, the paucity of complement activation may be a factor in the slower kinetics of progression of pathology in the 3xTg model of this disease.
Highlights
Complement proteins and activation products have been found associated with neuropathology in Alzheimer’s disease (AD)
C1q is associated with fibrillar plaques as well as tangles [3,8], and the presence of C5b-9 associated with dystrophic neurites in plaques and with tangles [9] indicates that complement is fully activated in AD [10]
These in vivo observations, supported by the in vitro studies demonstrating that fibrillar b-amyloid can activate the classical [11,12] and alternative [13] complement pathways and that the complement activation fragment C5a is chemotactic for microglia [14], led to the hypothesis that the complement activation triggered by fibrillar ß-amyloid contributes to the inflammatory reaction that can play a detrimental role in the progression of the later stages of Alzheimer’s disease [15]
Summary
Complement proteins and activation products have been found associated with neuropathology in Alzheimer’s disease (AD). Alzheimer’s disease is a progressive neurodegenerative dementia of the elderly characterized by a well defined pathology that includes accumulation of b-amyloid in plaques, hyperphosphorylated tau that forms neurofibrillary tangles, and neuronal loss [1] In addition to these hallmarks, a prominent inflammatory reaction, characterized by the presence of reactive glia associated with the fibrillar plaques, upregulation of several complement proteins [2,3,4,5] including local synthesis of the components [6,7] is observed. 3xTg mice, a mouse model of AD that develops neurofibrillar tangles as well as plaques, treated showed a decrease in plaques, reactive glia and, in addition, a decrease in hyperphosphoryated tau [18] These results support the hypothesis that complement activation plays a detrimental role in AD since inhibiting classical complement activation or blocking the downstream pathway by inhibiting C5a/C5aR interaction renders a substantial improvement in pathology and behavior of these animals
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