Increased complement biosynthesis by microglia and complement activation on neurons in Huntington's disease

In this study complement activation and biosynthesis have been analysed in the brains of Huntington's disease (HD) (n = 9) and normal (n = 3) individu als. In HD striatum, neurons, myelin and astrocytes were strongly stained w ith antibodies to C1q, C4, C3, iC3b-neoepitope and C9-neoepitope. In contra st, no staining for complement components was found in the normal striatum. Marked astrogliosis and microgliosis were observed in all HD caudate and t he internal capsule samples but not in normal brain. RT-PCR analysis and in -situ hybridisation were carried out to determine whether complement was sy nthesised locally by activated glial cells. By RT-PCR, we found that comple ment activators of the classical pathway C1q C chain, C1r, C4, C3, as well as the complement regulators, C1 inhibitor, clusterin, MCP, DAF, CD59, were all expressed constitutively and at much higher level in HD brains compare d to normal brain. Complement anaphylatoxin receptor mRNAs (C5a receptor an d C3a receptor) were strongly expressed in HD caudate. In general, we found that the level of complement mRNA in normal control brains was from 2 to 5 fold lower compared to HD striatum. Using in-situ hybridisation, we confir med that C3 mRNA and C9 mRNA were expressed by reactive microglia in RD int ernal capsule. We propose that complement produced locally by reactive micr oglia is activated on the membranes of neurons, contributing to neuronal ne crosis but also to proinflammatory activities. Complement opsonins (iC3b) a nd anaphylatoxins (C3a, C5a) may be involved in the recruitment and stimula tion of glial cells and phagocytes bearing specific complement receptors. ( C) 1999 Academic Press.