Complement in the brain

Abstract

The brain is considered to be an immune privileged site, because the blood-brain barrier limits entry of blood borne cells and proteins into the central nervous system (CNS). As a result, the detection and clearance of invading microorganisms and senescent cells as well as surplus neurotransmitters, aged and glycated proteins, in order to maintain a healthy environment for neuronal and glial cells, is largely confined to the innate immune system. In recent years it has become clear that many factors of innate immunity are expressed throughout the brain. Neuronal and glial cells express Toll like receptors as well as complement receptors, and virtually all complement components can be locally produced in the brain, often in response to injury or developmental cues. However, as inflammatory reactions could interfere with proper functioning of the brain, tight and fine tuned regulatory mechanisms are warranted. In age related diseases, such as Alzheimer's disease (AD), accumulating amyloid proteins elicit complement activation and a local, chronic inflammatory response that leads to attraction and activation of glial cells that, under such activation conditions, can produce neurotoxic substances, including pro-inflammatory cytokines and oxygen radicals. This process may be exacerbated by a disturbed balance between complement activators and complement regulatory proteins such as occurs in AD, as the local synthesis of these proteins is differentially regulated by pro-inflammatory cytokines. Much knowledge about the role of complement in neurodegenerative diseases has been derived from animal studies with transgenic overexpressing or knockout mice for specific complement factors or receptors. These studies have provided insight into the potential therapeutic use of complement regulators and complement receptor antagonists in chronic neurodegenerative diseases as well as in acute conditions, such as stroke. Interestingly, recent animal studies have also indicated that complement activation products are involved in brain development and synapse formation. Not only are these findings important for the understanding of how brain development and neural network formation is organized, it may also give insights into the role of complement in processes of neurodegeneration and neuroprotection in the injured or aged and diseased adult central nervous system, and thus aid in identifying novel and specific targets for therapeutic intervention.

Figure 1. Complement activation and regulation

Binding of the C1 macromolecule to the immune complexes, DNA, SAP and Aβ can initiate the CP, binding of mannose-binding lectin (MBL) or ficolins, complexed with a homodimer of MASP2, to carbohydrates (on bacterial cell walls) or attachment of spontaneously hydrolyzed C3 via active thio-ester to permissive surfaces or to properdin bound to an activating surface, generates a C3 convertase (C4b2a or C3bBb), and subsequently C5 convertases (C4b2a3b or C3bBb3b). Soluble and membrane-bound complement inhibitors regulate C activation. The soluble inhibitors C1-Inhibitor regulates activated C1, while factor I (fI) and C4b-binding protein (C4bp) control activation at the C4 and C3 level of the CP and LP, and fI together with factor H (fH) at the C3 and C5 convertase level of the AP. In addition, the membrane bound inhibitors CD35 and CD46 act as co-factors for fI, and CD55, decay accelerating factor (DAF) that accelerates the decay of C3 convertases. The fluid phase regulators vitronectin and clusterin and the membrane bound regulator CD59 can prevent formation of the C5b-9 complex on host cell membranes.

Figure 2. Complement proteins C1q and C3 are associated with plaque structures in human AD and in transgenic mouse models of AD

C1q immunostaining (brown) in hippocampus of an AD case (90 years old) (top left) and in cortex of 20 mo Tg2576 (bottom left) using anti human (Dako) and anti mouse (1151) C1q antibodies respectively. Activated C3 immunostaining in frontal cortex of an 68 year old AD case (Dako, red, top right) and in cortex of an 18m Tg2576 (brown, bottom right) using an anti human C3d and an anti mouse C3b/iC3b/C3c (2/11, Hycult) antibody respectively. Scale bar: 50 um. Photomicrographs courtesy of Dr. M.I. Fonseca, UC, Irvine.