Inflammation, autotoxicity and Alzheimer disease

McGeer, Patrick L.; McGeer, Edith G.

doi:10.1016/s0197-4580(01)00289-5

Cited by 434 publications

(265 citation statements)

References 76 publications

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“…Frequently in CNS diseases, sustained inflammation is the cause of tissue damage and associated pathology (Chavarria and Alcocer-Varela, 2004). The neuroinflammatory responses involve infiltrating peripheral cells of the immune system and nervous tissue cells, all participating in a complex orchestration of coagulation factors, complement, proteases and among others cytokines predominantly with a Th1 phenotype (McGeer and McGeer, 2001). Although TLR signaling results in inflammatory/Th1 responses in the peripheral organs (Aliprantis et al, 1999;Brightbill et al, 1999;Dabbagh and Lewis, 2003;Pulendran, 2004) their role in the CNS is largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Expression and distribution of Toll‐like receptors in the brain during murine neurocysticercosis

Mishra

Teale

2006

Journal of Neuroimmunology

148

153

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In a mouse model of neurocysticercosis, the expression and distribution of Toll like receptors (TLRs) was investigated by using both gene array analyses and in situ immunofluoresence microscopy (IF). In the normal uninfected brain, mRNA of all the TLRs are constitutively expressed albeit TLR5, TLR7, TLR8 and TLR9 to a lesser extent. In these animals, however, expression of TLR1, TLR3, TLR4 and TLR9 proteins was not detected. In contrast, parasite infection increased both gene and protein level expression of all the TLRs several fold except TLR5 where only the mRNA was upregulated. Importantly, TLRs were differentially distributed among various central nervous system (CNS) cell types and infiltrating leukocytes. TLR2 was almost exclusively localized to nervous tissue cells, particularly astrocytes, while TLR1 and TLR9 proteins were essentially limited to infiltrating leukocytes. All other TLRs tested were detected in both CNS and immune cell types. Interestingly, ependymal cells and neurofilaments of the cerebellar white matter of infected mice exhibited a substantial upregulation of TLR7 and TLR8 protein respectively. These data provide a comprehensive analysis of TLR expression in the normal and parasite infected brain and suggest a role for TLRs in the interplay of immune cells and CNS cells during infection.

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Section: Discussionmentioning

confidence: 99%

Expression and distribution of Toll‐like receptors in the brain during murine neurocysticercosis

Mishra

Teale

2006

Journal of Neuroimmunology

148

153

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“…These immune cells of monocytic lineage are activated by a wide range of stimuli and release pro-inflammatory mediators that, in turn, induce microglial autoactivation, thereby amplifying the inflammatory response. It has been proposed that elevated levels of ␤-amyloid in AD brain induces microglial activation and consequent release of pro-inflammatory cytokines, chemokines, and other potentially neurotoxic substances (5)(6)(7)(8)(9). Indeed, activated microglia can cause neuronal cell death in vitro (10 -13).…”

Section: Studies Using Mk2mentioning

confidence: 99%

MAPK-activated Protein Kinase 2 Deficiency in Microglia Inhibits Pro-inflammatory Mediator Release and Resultant Neurotoxicity

Culbert

Skaper

Howlett

et al. 2006

Journal of Biological Chemistry

151

106

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“…The main pathological hallmarks include senile amyloid plaques, neurofibrillary tangles, dystrophic neurites, significant neuronal loss in selected regions of the brain, and a chronic inflammatory response characterized by activated microglia, reactive astrocytes, complement factors, and increased expression of inflammatory cytokines (2)(3)(4). Chronic inflammation plays an important role in AD pathogenesis because numerous epidemiological studies have revealed significant protective effects of nonsteroidal anti-inflammatory drugs (5)(6)(7)(8)(9)(10).…”

Section: Alzheimer's Disease (Ad)mentioning

confidence: 99%

Identification of Cathepsin B as a Mediator of Neuronal Death Induced by Aβ-activated Microglial Cells Using a Functional Genomics Approach

Gan¹,

Ye²,

Chu³

et al. 2004

Journal of Biological Chemistry

125

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Alzheimer's disease is a progressive neurodegenerative disease characterized by senile plaques, neurofibrillary tangles, dystrophic neurites, and reactive glial cells. Activated microglia are found to be intimately associated with senile plaques and may play a central role in mediating chronic inflammatory conditions in Alzheimer's disease. Activation of cultured murine microglial BV2 cells by freshly sonicated A␤42 results in the secretion of neurotoxic factors that kill primary cultured neurons. To understand molecular pathways underlying A␤-induced microglial activation, we analyzed the expression levels of transcripts isolated from A␤42-activated BV2 cells using high density filter arrays. The analysis of these arrays identified 554 genes that are transcriptionally up-regulated by A␤42 in a statistically significant manner. Quantitative reverse transcription-PCR was used to confirm the regulation of a subset of genes, including cysteine proteases cathepsin B and cathepsin L, tissue inhibitor of matrix metalloproteinase 2, cytochrome c oxidase, and allograft inflammatory factor 1. Small interfering RNA-mediated silencing of the cathepsin B gene in A␤-activated BV2 cells diminished the microglial activation-mediated neurotoxicity. Moreover, CA-074, a specific cathepsin B inhibitor, also abolished the neurotoxic effects caused by A␤42-activated BV2 cells. Our results suggest an essential role for secreted cathepsin B in neuronal death mediated by A␤-activated inflammatory response.

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Inflammation, autotoxicity and Alzheimer disease

Cited by 434 publications

References 76 publications

Expression and distribution of Toll‐like receptors in the brain during murine neurocysticercosis

Expression and distribution of Toll‐like receptors in the brain during murine neurocysticercosis

MAPK-activated Protein Kinase 2 Deficiency in Microglia Inhibits Pro-inflammatory Mediator Release and Resultant Neurotoxicity

Identification of Cathepsin B as a Mediator of Neuronal Death Induced by Aβ-activated Microglial Cells Using a Functional Genomics Approach

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