Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice

Abstract

Abnormal accumulation of ␤-amyloid (A␤) in Alzheimer's disease (AD) is associated with prominent brain inflammation. Whereas earlier studies concluded that this inflammation is detrimental, more recent animal data suggest that at least some inflammatory processes may be beneficial and promote A␤ clearance. Consistent with these observations, overproduction of transforming growth factor (TGF)-␤1 resulted in a vigorous microglial activation that was accompanied by at least a 50% reduction in A␤ accumulation in human amyloid precursor protein (hAPP) transgenic mice. In a search for inflammatory mediators associated with this reduced pathology, we found that brain levels of C3, the central component of complement and a key inflammatory protein activated in AD, were markedly higher in hAPP͞TGF-␤1 mice than in hAPP mice. To assess the importance of complement in the pathogenesis of AD-like disease in mice, we inhibited C3 activation by expressing soluble complement receptor-related protein y (sCrry), a complement inhibitor, in the brains of hAPP mice. A␤ deposition was 2-to 3-fold higher in 1-year-old hAPP͞sCrry mice than in age-matched hAPP mice and was accompanied by a prominent accumulation of degenerating neurons. These results indicate that complement activation products can protect against A␤-induced neurotoxicity and may reduce the accumulation or promote the clearance of amyloid and degenerating neurons. These findings provide evidence for a role of complement and innate immune responses in AD-like disease in mice and support the concept that certain inflammatory defense mechanisms in the brain may be beneficial in neurodegenerative disease.

Microglial Phagocytosis of Fibrillar β-Amyloid through a β1Integrin-Dependent Mechanism

“…The participation of FcR in A␤ phagocytosis is consistent with previous reports of enhanced phagocytosis of A␤-IgG conjugates in vitro (Paresce et al, 1996;Brazil et al, 2000). The requirement of FcR for removal of A␤ deposits in vivo has been contested (Das et al, 2003), and there is clear evidence that alternative mechanisms are capable of removing A␤ deposits (Wyss-Coray et al, 2002;Wilcock et al, 2004).…”

“…The association of the complement component C1q with A␤ was reported to inhibit microglial phagocytosis (Webster et al, 2000) or enhance uptake if immune complexes were present (Webster et al, 2001). Wyss-Coray et al (2002) have recently shed significant new light on this issue by demonstrating that there is a complement-dependent process that is responsible for removing A␤ deposits from the brain. Mice overexpressing a complement inhibitor exhibited a dramatic increase of plaque deposition.…”

Gangliosides play pivotal roles in the regulation of complement systems and in the maintenance of integrity in nerve tissues

“…Besides roles in the induction of inflammation with complement activation and eventual neurodegeneration (23, 25), functions in development (32,33), neurogenesis in adults (34), and protection in disease-susceptible mutant mice like Tg/A␤ have been reported in ref. 35. In particular, physiological roles of complements such as the elimination of unnecessary degraded cell components or the refinement of the inf lammatory reaction have been reported in ref.…”

Microglial Phagocytosis Induced by Fibrillar β-Amyloid and IgGs Are Differentially Regulated by Proinflammatory Cytokines

“…These include the phagocytic uptake of A␤ through complementmediated mechanisms (Wyss-Coray et al, 2002) and through the fA␤ receptor complex (Koenigsknecht and Landreth, 2004), as well as trafficking of A␤ into the peripheral circulation through apolipoprotein-mediated uptake by vasculature (Zlokovic, 2004). We postulated that chronic inflammation in the AD brain suppresses activation of phagocytic machinery and affects the ability of microglial cells to mount a phagocytic response, thereby inhibiting normal microglial clearance of fA␤ and senile plaques.…”