Identification of cathepsin B as a mediator of neuronal death induced by Aβ-activated microglial cells using a functional genomics approach

被引：119

作者：

Gan, L ^{[1
]}

Ye, SM ^{[1
]}

Chu, A ^{[1
]}

Anton, K ^{[1
]}

Yi, SL ^{[1
]}

Vincent, VA ^{[1
]}

von Schack, D ^{[1
]}

Chin, D ^{[1
]}

Murray, J ^{[1
]}

Lohr, S ^{[1
]}

Patthy, L ^{[1
]}

Gonzalez-Zulueta, M ^{[1
]}

Nikolich, K ^{[1
]}

Urfer, R ^{[1
]}

机构：

[1] AGY Therapeut Inc, San Francisco, CA 94080 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2004年 / 279卷 / 07期

关键词：

D O I：

10.1074/jbc.M306183200

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 beta 42 results in the secretion of neurotoxic factors that kill primary cultured neurons. To understand molecular pathways underlying Abeta- induced microglial activation, we analyzed the expression levels of transcripts isolated from Abeta42- activated BV2 cells using high density filter arrays. The analysis of these arrays identified 554 genes that are transcriptionally up- regulated by Abeta42 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 beta- 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 beta 42- activated BV2 cells. Our results suggest an essential role for secreted cathepsin B in neuronal death mediated by Abeta-activated inflammatory response.

引用

页码：5565 / 5572

页数：8

共 57 条

[31]

McDonald DR, 1997, J NEUROSCI, V17, P2284

[32] Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: A review of 17 epidemiologic studies [J].