Histological and Direct Evidence for the Role of Complement in the Neuroinflammation of AD

Abstract

In Alzheimers's disease (AD) a disturbed balance between synthesis and removal of Aβ leads to the formation of Aβ deposits and a reaction of the innate immune system. Little evidence exists for a contribution of the adaptive immune response in AD, as no signs of influx of blood borne cells or presence of immunoglobulins in Aβ deposits are apparent. Factors of the complement(C) system and pentraxins act as pattern recognition molecules and mediate uptake of Aβ by glial cells expressing C-receptors (Crec). These interactions may, however, also lead to synthesis and secretion of reactive oxygen species (ROS), cytokines, chemokines and other potentially neurotoxic agents by the glial cells. Virtually all complement factors are produced in brain, and the expression is increased in AD affected brain areas. In AD brain areas with amyloid deposits especially classical pathway C activation products are readily observed. Also C regulatory proteins (Creg) and Crec can be found in the brain parenchyma and are upregulated, especially under acute inflammatory conditions, such as meningitis. However, under chronic low-grade inflammatory conditions, such as in AD, Creg and to some extent Crec expression may remain at a low level, thereby allowing C activation to proceed, leading to sustained activation of glial cells and neurodegenerative changes. In this review evidence from immunohistochemical, in vitro and animal studies pointing to a role for C activation is discussed, with special focus on the disturbed balance between C activators and Cregs in AD.

Ibuprofen targets neuronal pentraxins expresion and improves cognitive function in mouse model of AlCl3-induced neurotoxicity

“…Neuronal pentraxins (NPs), which have key roles in neuroinflammation (15), belong to a family of proteins that are homologous to immune system proteins, including C-reactive and acute phase proteins, and are believed to be involved in synaptic functions (16). The NPs, including NP1, NP2 and NP receptor (NPR) (17), are proteins that were initially identified due to their ability to bind to the snake poison taipoxin (18) and mediate its internalization, leading to cell death.…”

Animal models of Alzheimer disease: historical pitfalls and a path forward

“…Aβ1-42 is more prone to oligomerization and more readily forms the aggregates present in AD (Schroeter et al, 2003;Cai et al, 2001;Iwatsubo et al, 1994). Deposition of Aβ plaques in the brain is also associated with neuronal damage and activation of local astrocytes and microglia, resulting in localized inflammatory responses (Veerhuis, 2011;Eikelenboom and Stam, 1982;Eikelenboom et al, 1989;Eikelenboom and Veerhuis, 1996;Rosenberg, 2005). However, accumulation of Aβ plaques is not necessarily either a cause or a consequence of AD, as plaques can be found in the brains of cognitively healthy individuals (Walsh et al, 2000).…”

Review article What causes alzheimer’s disease?

“…Complement proteins associated with the 'classical' pathway [123], brain reactive antibodies [132], immunoglobulins [62,95], circulating immune complexes (CIC) in peripheral tissue and cerebral blood vessels [86], helper/inducer and cytotoxic/ suppressor T-cells [123], and abundant reactive microglia [123] have all been observed in AD. Complement system proteins may act as pattern recognition molecules mediating the uptake of Ab by glial cells which express complement receptors [195]. Significant alterations in the major histocompatibility locus (MHC) antigens have also been demonstrated [197] suggesting either increased resistance or susceptibility to an antigen in AD [50,88].…”