Title Differential regulation of A beta 42-induced neuronal C 1 q synthesis and microglial activation

Expression of C1q, an early component of the classical complement pathway, has been shown to be induced in neurons in hippocampal slices, following accumulation of exogenous Aβ42. Microglial activation was also detected by surface marker expression and cytokine production. To determine whether C1q induction was correlated with intraneuronal Aβ and/or microglial activation, D-(-)-2amino-5-phosphonovaleric acid (APV, an NMDA receptor antagonist) and glycine-arginine-glycineaspartic acid-serine-proline peptide (RGD, an integrin receptor antagonist), which blocks and enhances Aβ42 uptake, respectively, were assessed for their effect on neuronal C1q synthesis and microglial activation. APV inhibited, and RGD enhanced, microglial activation and neuronal C1q expression. However, addition of Aβ10–20 to slice cultures significantly reduced Aβ42 uptake and microglial activation, but did not alter the Aβ42-induced neuronal C1q expression. Furthermore, Aβ10–20 alone triggered C1q production in neurons, demonstrating that neither neuronal Aβ42 accumulation, nor microglial activation is required for neuronal C1q upregulation. These data are compatible with the hypothesis that multiple receptors are involved in Aβ injury and signaling in neurons. Some lead to neuronal C1q induction, whereas other(s) lead to intraneuronal accumulation of Aβ and/or stimulation of microglia. Introduction Alzheimer's disease (AD) is the most common form of dementia in the elderly. Its main pathological features include extracellular amyloid beta (Aβ) deposition in plaques, neurofibrillary tangles (composed of hyperphosphorylated tau protein) in neurons, progressive loss of synapses and cortical/hippocampal neurons, and upregulation of inflammatory components including activated microglia and astrocytes and complement activation [1]. Although the contribution of abnormal phosphorylation and assembly of tau to AD dementia remains a focus of investigation, therapies that interfere with Aβ production, enhance its degradation, or cause its clearance from the central nervous system (CNS) have been the center of many studies in search of a cure for this disease. Microglial cells, when activated, are believed to be responsible for much of the Aβ clearance through receptor-mediated phagocytosis [2,3]. Upon activation, microglia acquire features more characteristic of macrophages, including high phagocytic activity, increased expression of leukocyte common antigen (CD45), major histocompatibility complex (MHC) class II and costimulatory molecules B7, and secretion of proinflammatory substances [4]. In addition, phagocytic microglia also participate in the removal of degenerating neurons and synapses as well Published: 10 January 2005 Journal of Neuroinflammation 2005, 2:1 doi:10.1186/1742-2094-2-1 Received: 18 November 2004 Accepted: 10 January 2005 This article is available from: http://www.jneuroinflammation. com/content/2/1/1 © 2005 Fan and Tenner; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.