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Identification of plexin A4 as a novel clusterin receptor links two Alzheimer’s disease risk genes
Although abundant genetic and biochemical evidence strongly links Clusterin (CLU) to Alzheimer disease (AD) pathogenesis, the receptor for CLU within the adult brain is currently unknown. Using unbiased approaches, we identified Plexin A4 (PLXNA4) as a novel, high-affinity receptor for CLU in the ad...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5179943/ https://www.ncbi.nlm.nih.gov/pubmed/27378688 http://dx.doi.org/10.1093/hmg/ddw188 |
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author | Kang, Silvia S. Kurti, Aishe Wojtas, Aleksandra Baker, Kelsey E. Liu, Chia-Chen Kanekiyo, Takahisa Deming, Yuetiva Cruchaga, Carlos Estus, Steven Bu, Guojun Fryer, John D. |
author_facet | Kang, Silvia S. Kurti, Aishe Wojtas, Aleksandra Baker, Kelsey E. Liu, Chia-Chen Kanekiyo, Takahisa Deming, Yuetiva Cruchaga, Carlos Estus, Steven Bu, Guojun Fryer, John D. |
author_sort | Kang, Silvia S. |
collection | PubMed |
description | Although abundant genetic and biochemical evidence strongly links Clusterin (CLU) to Alzheimer disease (AD) pathogenesis, the receptor for CLU within the adult brain is currently unknown. Using unbiased approaches, we identified Plexin A4 (PLXNA4) as a novel, high-affinity receptor for CLU in the adult brain. PLXNA4 protein expression was high in brain with much lower levels in peripheral organs. CLU protein levels were significantly elevated in the cerebrospinal fluid (CSF) of Plxna4(-/-) mice and, in humans, CSF levels of CLU were also associated with PLXNA4 genotype. Human AD brains had significantly increased the levels of CLU protein but decreased levels of PLXNA4 by ∼50%. To determine whether PLXNA4 levels influenced cognition, we analyzed the behaviour of Plxna4(+/+), Plxna4(+/-), and Plxna4(-/-) mice. In comparison to WT controls, both Plxna4(+/-) and Plxna4(-/-) mice were hyperactive in the open field assay while Plxna4(-/-) mice displayed a hyper-exploratory (low-anxiety phenotype) in the elevated plus maze. Importantly, both Plxna4(+/-) and Plxna4(-/-) mice displayed prominent deficits in learning and memory in the contextual fear-conditioning paradigm. Thus, even a 50% reduction in the level of PLXNA4 is sufficient to cause memory impairments, raising the possibility that memory problems seen in AD patients could be due to reductions in the level of PLXNA4. Both CLU and PLXNA4 have been genetically associated with AD risk and our data thus provide a direct relationship between two AD risk genes. Our data suggest that increasing the levels of PLXNA4 or targeting CLU-PLXNA4 interactions may have therapeutic value in AD. |
format | Online Article Text |
id | pubmed-5179943 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-51799432016-12-27 Identification of plexin A4 as a novel clusterin receptor links two Alzheimer’s disease risk genes Kang, Silvia S. Kurti, Aishe Wojtas, Aleksandra Baker, Kelsey E. Liu, Chia-Chen Kanekiyo, Takahisa Deming, Yuetiva Cruchaga, Carlos Estus, Steven Bu, Guojun Fryer, John D. Hum Mol Genet Articles Although abundant genetic and biochemical evidence strongly links Clusterin (CLU) to Alzheimer disease (AD) pathogenesis, the receptor for CLU within the adult brain is currently unknown. Using unbiased approaches, we identified Plexin A4 (PLXNA4) as a novel, high-affinity receptor for CLU in the adult brain. PLXNA4 protein expression was high in brain with much lower levels in peripheral organs. CLU protein levels were significantly elevated in the cerebrospinal fluid (CSF) of Plxna4(-/-) mice and, in humans, CSF levels of CLU were also associated with PLXNA4 genotype. Human AD brains had significantly increased the levels of CLU protein but decreased levels of PLXNA4 by ∼50%. To determine whether PLXNA4 levels influenced cognition, we analyzed the behaviour of Plxna4(+/+), Plxna4(+/-), and Plxna4(-/-) mice. In comparison to WT controls, both Plxna4(+/-) and Plxna4(-/-) mice were hyperactive in the open field assay while Plxna4(-/-) mice displayed a hyper-exploratory (low-anxiety phenotype) in the elevated plus maze. Importantly, both Plxna4(+/-) and Plxna4(-/-) mice displayed prominent deficits in learning and memory in the contextual fear-conditioning paradigm. Thus, even a 50% reduction in the level of PLXNA4 is sufficient to cause memory impairments, raising the possibility that memory problems seen in AD patients could be due to reductions in the level of PLXNA4. Both CLU and PLXNA4 have been genetically associated with AD risk and our data thus provide a direct relationship between two AD risk genes. Our data suggest that increasing the levels of PLXNA4 or targeting CLU-PLXNA4 interactions may have therapeutic value in AD. Oxford University Press 2016-08-15 2016-07-04 /pmc/articles/PMC5179943/ /pubmed/27378688 http://dx.doi.org/10.1093/hmg/ddw188 Text en © The Author 2016. Published by Oxford University Press. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Kang, Silvia S. Kurti, Aishe Wojtas, Aleksandra Baker, Kelsey E. Liu, Chia-Chen Kanekiyo, Takahisa Deming, Yuetiva Cruchaga, Carlos Estus, Steven Bu, Guojun Fryer, John D. Identification of plexin A4 as a novel clusterin receptor links two Alzheimer’s disease risk genes |
title | Identification of plexin A4 as a novel clusterin receptor links two Alzheimer’s disease risk genes |
title_full | Identification of plexin A4 as a novel clusterin receptor links two Alzheimer’s disease risk genes |
title_fullStr | Identification of plexin A4 as a novel clusterin receptor links two Alzheimer’s disease risk genes |
title_full_unstemmed | Identification of plexin A4 as a novel clusterin receptor links two Alzheimer’s disease risk genes |
title_short | Identification of plexin A4 as a novel clusterin receptor links two Alzheimer’s disease risk genes |
title_sort | identification of plexin a4 as a novel clusterin receptor links two alzheimer’s disease risk genes |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5179943/ https://www.ncbi.nlm.nih.gov/pubmed/27378688 http://dx.doi.org/10.1093/hmg/ddw188 |
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