Neurons express proteins of the classical complement pathway in Alzheimer disease

Terai, Kazuhiro; Walker, Douglas G.; McGeer, Edith G.; McGeer, Patrick L.

doi:10.1016/s0006-8993(97)00849-4

Cited by 130 publications

(83 citation statements)

References 18 publications

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“…In addition to the systemic complement system, there are also complete features of the complement system in CNS; that is, complement factors, complement receptors (22,23), and complement regulators (24). Not only glial cells such as astrocytes and microglia, but also neurons can generate these molecules (13,22,23).…”

Section: Discussionmentioning

confidence: 99%

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Gangliosides play pivotal roles in the regulation of complement systems and in the maintenance of integrity in nerve tissues

Ohmi¹,

Tajima

Ohkawa³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

124

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Gangliosides are considered to be essential in the maintenance and repair of nervous tissues; however, the mechanisms for neurodegeneration caused by ganglioside defects are unknown. We examined gene expression profiles in double knockout (DKO) mice of GM2/GD2 synthase and GD3 synthase genes and showed that the majority of complement genes and their receptors were up-regulated in cerebellum in DKO mice. Inflammatory reactions were demonstrated in those tissues by measuring up-regulated inflammatory cytokines, indicating the presence of complement activation and inflammation as reported in Alzheimer's disease. Immunoblotting of fractionated membrane extracts by sucrose density gradient revealed that complement-regulatory molecules such as decay-accelerating factor and CD59 were dispersed from glycolipid-enriched microdomain/rafts in DKO cerebellum. Immunohistostaining of these molecules showed disordered membrane localization. These results suggested that dysfunction of complement-regulatory molecules may be due to abnormal glycolipid-enriched microdomain/rafts that triggered complement activation, subsequent inflammation, and neurodegeneration in DKO mice. Generation of the triple KO mice lacking complement activity in addition to the two glycosyltransferases suggested that complement activation is involved in the inflammatory reactions and neurodegeneration caused by the ganglioside deficiency.cerebellum ͉ degeneration ͉ inflammation ͉ knockout ͉ lipid raft

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Section: Discussionmentioning

confidence: 99%

“…All components of the classical complement pathway have been identified in neurons (13), and this pathway has been reported to be activated in AD by fibrillar ␤ amyloid peptide (14) or neurofibrillary tangles (15). The detection and activation of the alternative pathway in AD has also been reported (16).…”

mentioning

confidence: 99%

Gangliosides play pivotal roles in the regulation of complement systems and in the maintenance of integrity in nerve tissues

Ohmi¹,

Tajima

Ohkawa³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

124

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“…Complement activation has been associated with several neurodegenerative diseases, including ALS, Parkinson's and Alzheimer's (31)(32)(33)(34)(35) and analysis of entire spinal cords from mutant SOD1 G93A mice showed transcriptional up-regulation of complement components at early symptomatic stages (10). C1q components have also previously been suggested to be produced by injured or stressed neurons, especially in Alzheimer's disease (36)(37)(38)(39)(40). Furthermore, deletion of C1q has been shown to reduce pathological signs in APP-transgenic Alzheimer-mice (41).…”

Section: Discussionmentioning

confidence: 99%

Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons

Lobsiger

Boillée

Cleveland

2007

Proc. Natl. Acad. Sci. U.S.A.

133

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Global, age-dependent changes in gene expression from rodent models of inherited ALS caused by dominant mutations in superoxide-dismutase 1 (SOD1) were identified by using gene arrays and RNAs isolated from purified embryonic and adult motor neurons. Comparison of embryonic motor neurons expressing a dismutase active ALS-linked mutant SOD1 with those expressing comparable levels of wild-type SOD1 revealed the absence of mutant-induced mRNA changes. An age-dependent mRNA change that developed presymptomatically in adult motor neurons collected by laser microdissection from mice expressing dismutase active ALS-linked mutants was dysregulation of the D/L-serine biosynthetic pathway, previously linked to both excitotoxic and neurotrophic effects. An unexpected dysregulation common to motor neurons expressing either dismutase active or inactive mutants was induction of neuronally derived components of the classic complement system and the regenerative/injury response. Alteration of these mutant SOD1-induced pathways identified a set of targets for therapies for inherited ALS.amyotrophic lateral sclerosis ͉ gene expression profile ͉ laser microdissection A myotrophic lateral sclerosis (ALS) is a fatal, adult-onset neurodegenerative disease that selectively kills brain and spinal cord motor neurons (reviewed in ref. 1). Although most ALS cases are sporadic and of unknown origin, some familial instances are caused by acquired toxic properties of dominant missense point mutations in the ubiquitously expressed superoxide dismutase 1 (SOD1) independent of its dismutase activity (2, 3). Because both familial and sporadic forms lead to what is nearly indistinguishable diseases, the analysis of mutant (human or mouse) SOD1-overexpressing rodent ALS models, which develop a fatal, late-onset, progressive ALS-like paralysis (4-7), can provide valuable tools for dissecting the overall ALS disease mechanism.The central question in understanding ALS in mutant SOD1-expressing mouse and rat models is what are the slowly acting toxic mechanisms, or build-up of toxic products that are responsible for ultimately leading to the degeneration of the most at-risk cell type, the large spinal cord motor neurons (1). Such properties of mutant SOD1 seem likely to induce responses in the genes expressed by motor neurons (their transcriptome) at early disease stages or even before obvious clinical symptoms. Identifying the manner in which motor neurons respond to, or are affected by, ALS-linked mutant SOD1-induced damage could provide key insights either into primary mechanisms of toxicity or to potential therapeutic approaches that may be successful in slowing disease progression in ALS.High-density oligonucleotide microarrays provide an excellent tool to test on a genome wide level the effects of candidate events on the cellular expression profile. Because certain aspects of ALS are non-cell autonomous and originate from mutant SOD1 accumulation in non-motor neuronal cells (8, 9), cell-type specificity is of high importance when using such an a...

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“…In fact, there is evidence that in the course of cerebrovascular disease and Alzheimer's disease, serum proteins like Ig, fibrinogen, and complement factors are deposited in the brain parenchyma (41). Although there is accumulating evidence for enhanced cerebral biosynthesis of C1q in Alzheimer's disease brain, based on Northern blot, RT-PCR, and Western blot results, the issue of neuronal vs nonneuronal biosynthesis of C1q in normal human brains and in Alzheimer's disease brains is still controversial (2,5,7,8,41,42). Likewise, in experimental studies of different types of inflammatory and neurodegenerative brain lesions, the neuronal vs nonneuronal biosynthesis of C1q is a matter of controversy (21, 22, 24 -27).…”

Section: Discussionmentioning

confidence: 99%

Complement C1q Is Dramatically Up-Regulated in Brain Microglia in Response to Transient Global Cerebral Ischemia

Schäfer

Schwaeble

Post

et al. 2000

The Journal of Immunology

149

108

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Recent evidence suggests that the pathophysiology of neurodegenerative and inflammatory neurological diseases has a neuroimmunological component involving complement, an innate humoral immune defense system. The present study demonstrates the effects of experimentally induced global ischemia on the biosynthesis of C1q, the recognition subcomponent of the classical complement activation pathway, in the CNS. Using semiquantitative in situ hybridization, immunohistochemistry, and confocal laser scanning microscopy, a dramatic and widespread increase of C1q biosynthesis in rat brain microglia (but not in astrocytes or neurons) within 24 h after the ischemic insult was observed. A marked increase of C1q functional activity in cerebrospinal fluid taken 1, 24, and 72 h after the ischemic insult was determined by C1q-dependent hemolytic assay. In the light of the well-established role of complement and complement activation products in the initiation and maintenance of inflammation, the ischemia-induced increase of cerebral C1q biosynthesis and of C1q functional activity in the cerebrospinal fluid implies that the proinflammatory activities of locally produced complement are likely to contribute to the pathophysiology of cerebral ischemia. Pharmacological modulation of complement activation in the brain may be a therapeutic target in the treatment of stroke.

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Neurons express proteins of the classical complement pathway in Alzheimer disease

Cited by 130 publications

References 18 publications

Gangliosides play pivotal roles in the regulation of complement systems and in the maintenance of integrity in nerve tissues

Gangliosides play pivotal roles in the regulation of complement systems and in the maintenance of integrity in nerve tissues

Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons

Complement C1q Is Dramatically Up-Regulated in Brain Microglia in Response to Transient Global Cerebral Ischemia

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