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Implication of Complement System and Its Regulators in Alzheimer's Disease

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Implication of Complement System and Its Regulators in Alzheimer's Disease

Martin V Kolev et al. Curr Neuropharmacol.

Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disease that affects approximately 24 million people worldwide. A number of different risk factors have been implicated in AD, however, neuritic (amyloid) plaques are considered as one of the defining risk factors and pathological hallmarks of the disease. Complement proteins are integral components of amyloid plaques and cerebral vascular amyloid in Alzheimer brains. They can be found at the earliest stages of amyloid deposition and their activation coincides with the clinical expression of Alzheimer's dementia. This review emphasizes on the dual key roles of complement system and complement regulators (CRegs) in disease pathology and progression. The particular focus of this review is on currently evolving strategies for design of complement inhibitors that might aid therapy by restoring the fine balance between activated components of complement system, thus improving the cognitive performance of patients. This review discusses these issues with a view to inspiring the development of new agents that could be useful for the treatment of AD.

Keywords: Alzheimer’s disease; CD59; complement; complement regulators; complement therapeutics.; inflammation; neurodegeneration; β-amyloid peptide.

Figures

Fig. (1)
Fig. (1)
The complement system in AD. Binding of C1q and C3 to amyloid plaques can activate the classical and alternative pathways of complement system. No binding of MBL to amyloid plaques and activation of the lectin pathway has been reported. Activation of complement results in cleavage of C3 and C5 by specific enzymes (C3- and C5-convertases) followed by formation of membrane attack complex and cell lysis. Complement is regulated by soluble and membrane bound complement regulators shown in gray boxes.

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