Dual role of cofilin in APP trafficking and amyloid-β clearance
The accumulation of amyloid-β (Aβ) plays a pivotal early event in the pathogenesis of Alzheimer's disease (AD). In the brain, neurons produce Aβ by the proteolytic processing of amyloid precursor protein (APP) through the endocytic pathway, whereas microglia mediate Aβ clearance also endocytic...
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Published in | The FASEB journal Vol. 33; no. 12; p. 14234 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
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01.12.2019
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Abstract | The accumulation of amyloid-β (Aβ) plays a pivotal early event in the pathogenesis of Alzheimer's disease (AD). In the brain, neurons produce Aβ by the proteolytic processing of amyloid precursor protein (APP) through the endocytic pathway, whereas microglia mediate Aβ clearance also
endocytic mechanisms. Previous studies have shown the critical importance of cofilin, a filamentous actin-severing protein, in actin dynamics and pathogen-triggered endocytic processes. Moreover, the binding of Aβ42 oligomers to β1-integrin triggers the cofilin activation, and in turn, cofilin promotes the internalization of surface β1-integrin. However, a role for cofilin in APP processing and Aβ metabolism has not been investigated. In this study, we found that knockdown of cofilin in Chinese hamster ovary 7WD10 cells and primary neurons significantly reduces Aβ production by increasing surface APP (sAPP) levels. Expression of active (S3A) but not inactive (S3E) cofilin reduces sAPP levels by enhancing APP endocytosis. Accordingly, Aβ deposition in APP and presenilin 1 (PS1) transgenic mice is significantly reduced by genetic reduction of cofilin (APP/PS1;cofilin
). However, the reduction of Aβ load in APP/PS1;cofilin
mice is paradoxically associated with significantly increased ionized calcium-binding adaptor molecule 1-positive microglial activation surrounding Aβ deposits. Primary microglia isolated from cofilin
mice demonstrate significantly enhanced state of activation and greater ability to uptake and clear Aβ42, which is reversed with the active (S3A) but not inactive (S3E) form of cofilin. These results taken together indicate a significant role for cofilin in Aβ accumulation
dual and opposing endocytic mechanisms of promoting Aβ production in neurons and inhibiting Aβ clearance in microglia.-Liu, T., Woo, J.-A. A., Yan, Y., LePochat, P., Bukhari, M. Z., Kang, D. E. Dual role of cofilin in APP trafficking and amyloid-β clearance. |
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AbstractList | The accumulation of amyloid-β (Aβ) plays a pivotal early event in the pathogenesis of Alzheimer's disease (AD). In the brain, neurons produce Aβ by the proteolytic processing of amyloid precursor protein (APP) through the endocytic pathway, whereas microglia mediate Aβ clearance also
endocytic mechanisms. Previous studies have shown the critical importance of cofilin, a filamentous actin-severing protein, in actin dynamics and pathogen-triggered endocytic processes. Moreover, the binding of Aβ42 oligomers to β1-integrin triggers the cofilin activation, and in turn, cofilin promotes the internalization of surface β1-integrin. However, a role for cofilin in APP processing and Aβ metabolism has not been investigated. In this study, we found that knockdown of cofilin in Chinese hamster ovary 7WD10 cells and primary neurons significantly reduces Aβ production by increasing surface APP (sAPP) levels. Expression of active (S3A) but not inactive (S3E) cofilin reduces sAPP levels by enhancing APP endocytosis. Accordingly, Aβ deposition in APP and presenilin 1 (PS1) transgenic mice is significantly reduced by genetic reduction of cofilin (APP/PS1;cofilin
). However, the reduction of Aβ load in APP/PS1;cofilin
mice is paradoxically associated with significantly increased ionized calcium-binding adaptor molecule 1-positive microglial activation surrounding Aβ deposits. Primary microglia isolated from cofilin
mice demonstrate significantly enhanced state of activation and greater ability to uptake and clear Aβ42, which is reversed with the active (S3A) but not inactive (S3E) form of cofilin. These results taken together indicate a significant role for cofilin in Aβ accumulation
dual and opposing endocytic mechanisms of promoting Aβ production in neurons and inhibiting Aβ clearance in microglia.-Liu, T., Woo, J.-A. A., Yan, Y., LePochat, P., Bukhari, M. Z., Kang, D. E. Dual role of cofilin in APP trafficking and amyloid-β clearance. |
Author | Yan, Yan Liu, Tian LePochat, Patrick Kang, David E Bukhari, Mohammed Zaheen Woo, Jung-A A |
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Snippet | The accumulation of amyloid-β (Aβ) plays a pivotal early event in the pathogenesis of Alzheimer's disease (AD). In the brain, neurons produce Aβ by the... |
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SubjectTerms | Alzheimer Disease - metabolism Amyloid beta-Peptides - genetics Amyloid beta-Peptides - metabolism Amyloid beta-Protein Precursor - genetics Amyloid beta-Protein Precursor - metabolism Amyloid Precursor Protein Secretases - genetics Amyloid Precursor Protein Secretases - metabolism Animals CHO Cells Cricetinae Cricetulus Gene Expression Regulation - physiology Gene Knockdown Techniques Mice Mice, Inbred Strains Mice, Transgenic Microglia - metabolism |
Title | Dual role of cofilin in APP trafficking and amyloid-β clearance |
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