Astrocyte-derived clusterin suppresses amyloid formation in vivo
Abstract Background Accumulation of amyloid-β (Aβ) peptide in the brain is a pathological hallmark of Alzheimer’s disease (AD). The clusterin (CLU) gene confers a risk for AD and CLU is highly upregulated in AD patients, with the common non-coding, protective CLU variants associated with increased e...
Main Authors: | , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
BMC
2020-11-01
|
Series: | Molecular Neurodegeneration |
Subjects: | |
Online Access: | https://doi.org/10.1186/s13024-020-00416-1 |
id |
doaj-7a11c0d2b8ee4e5f80e6c394f1d6eed1 |
---|---|
record_format |
Article |
spelling |
doaj-7a11c0d2b8ee4e5f80e6c394f1d6eed12020-11-29T12:12:18ZengBMCMolecular Neurodegeneration1750-13262020-11-0115111410.1186/s13024-020-00416-1Astrocyte-derived clusterin suppresses amyloid formation in vivoAleksandra M. Wojtas0Jonathon P. Sens1Silvia S. Kang2Kelsey E. Baker3Taylor J. Berry4Aishe Kurti5Lillian Daughrity6Karen R. Jansen-West7Dennis W. Dickson8Leonard Petrucelli9Guojun Bu10Chia-Chen Liu11John D. Fryer12Department of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicDepartment of Neuroscience, Mayo ClinicAbstract Background Accumulation of amyloid-β (Aβ) peptide in the brain is a pathological hallmark of Alzheimer’s disease (AD). The clusterin (CLU) gene confers a risk for AD and CLU is highly upregulated in AD patients, with the common non-coding, protective CLU variants associated with increased expression. Although there is strong evidence implicating CLU in amyloid metabolism, the exact mechanism underlying the CLU involvement in AD is not fully understood or whether physiologic alterations of CLU levels in the brain would be protective. Results We used a gene delivery approach to overexpress CLU in astrocytes, the major source of CLU expression in the brain. We found that CLU overexpression resulted in a significant reduction of total and fibrillar amyloid in both cortex and hippocampus in the APP/PS1 mouse model of AD amyloidosis. CLU overexpression also ameliorated amyloid-associated neurotoxicity and gliosis. To complement these overexpression studies, we also analyzed the effects of haploinsufficiency of Clu using heterozygous (Clu +/− ) mice and control littermates in the APP/PS1 model. CLU reduction led to a substantial increase in the amyloid plaque load in both cortex and hippocampus in APP/PS1; Clu +/− mice compared to wild-type (APP/PS1; Clu +/+ ) littermate controls, with a concomitant increase in neuritic dystrophy and gliosis. Conclusions Thus, both physiologic ~ 30% overexpression or ~ 50% reduction in CLU have substantial impacts on amyloid load and associated pathologies. Our results demonstrate that CLU plays a major role in Aβ accumulation in the brain and suggest that efforts aimed at CLU upregulation via pharmacological or gene delivery approaches offer a promising therapeutic strategy to regulate amyloid pathology.https://doi.org/10.1186/s13024-020-00416-1Alzheimer’s diseaseClusterinAβAmyloid plaquesAdeno-associated viral vectorsHaploinsufficiency |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Aleksandra M. Wojtas Jonathon P. Sens Silvia S. Kang Kelsey E. Baker Taylor J. Berry Aishe Kurti Lillian Daughrity Karen R. Jansen-West Dennis W. Dickson Leonard Petrucelli Guojun Bu Chia-Chen Liu John D. Fryer |
spellingShingle |
Aleksandra M. Wojtas Jonathon P. Sens Silvia S. Kang Kelsey E. Baker Taylor J. Berry Aishe Kurti Lillian Daughrity Karen R. Jansen-West Dennis W. Dickson Leonard Petrucelli Guojun Bu Chia-Chen Liu John D. Fryer Astrocyte-derived clusterin suppresses amyloid formation in vivo Molecular Neurodegeneration Alzheimer’s disease Clusterin Aβ Amyloid plaques Adeno-associated viral vectors Haploinsufficiency |
author_facet |
Aleksandra M. Wojtas Jonathon P. Sens Silvia S. Kang Kelsey E. Baker Taylor J. Berry Aishe Kurti Lillian Daughrity Karen R. Jansen-West Dennis W. Dickson Leonard Petrucelli Guojun Bu Chia-Chen Liu John D. Fryer |
author_sort |
Aleksandra M. Wojtas |
title |
Astrocyte-derived clusterin suppresses amyloid formation in vivo |
title_short |
Astrocyte-derived clusterin suppresses amyloid formation in vivo |
title_full |
Astrocyte-derived clusterin suppresses amyloid formation in vivo |
title_fullStr |
Astrocyte-derived clusterin suppresses amyloid formation in vivo |
title_full_unstemmed |
Astrocyte-derived clusterin suppresses amyloid formation in vivo |
title_sort |
astrocyte-derived clusterin suppresses amyloid formation in vivo |
publisher |
BMC |
series |
Molecular Neurodegeneration |
issn |
1750-1326 |
publishDate |
2020-11-01 |
description |
Abstract Background Accumulation of amyloid-β (Aβ) peptide in the brain is a pathological hallmark of Alzheimer’s disease (AD). The clusterin (CLU) gene confers a risk for AD and CLU is highly upregulated in AD patients, with the common non-coding, protective CLU variants associated with increased expression. Although there is strong evidence implicating CLU in amyloid metabolism, the exact mechanism underlying the CLU involvement in AD is not fully understood or whether physiologic alterations of CLU levels in the brain would be protective. Results We used a gene delivery approach to overexpress CLU in astrocytes, the major source of CLU expression in the brain. We found that CLU overexpression resulted in a significant reduction of total and fibrillar amyloid in both cortex and hippocampus in the APP/PS1 mouse model of AD amyloidosis. CLU overexpression also ameliorated amyloid-associated neurotoxicity and gliosis. To complement these overexpression studies, we also analyzed the effects of haploinsufficiency of Clu using heterozygous (Clu +/− ) mice and control littermates in the APP/PS1 model. CLU reduction led to a substantial increase in the amyloid plaque load in both cortex and hippocampus in APP/PS1; Clu +/− mice compared to wild-type (APP/PS1; Clu +/+ ) littermate controls, with a concomitant increase in neuritic dystrophy and gliosis. Conclusions Thus, both physiologic ~ 30% overexpression or ~ 50% reduction in CLU have substantial impacts on amyloid load and associated pathologies. Our results demonstrate that CLU plays a major role in Aβ accumulation in the brain and suggest that efforts aimed at CLU upregulation via pharmacological or gene delivery approaches offer a promising therapeutic strategy to regulate amyloid pathology. |
topic |
Alzheimer’s disease Clusterin Aβ Amyloid plaques Adeno-associated viral vectors Haploinsufficiency |
url |
https://doi.org/10.1186/s13024-020-00416-1 |
work_keys_str_mv |
AT aleksandramwojtas astrocytederivedclusterinsuppressesamyloidformationinvivo AT jonathonpsens astrocytederivedclusterinsuppressesamyloidformationinvivo AT silviaskang astrocytederivedclusterinsuppressesamyloidformationinvivo AT kelseyebaker astrocytederivedclusterinsuppressesamyloidformationinvivo AT taylorjberry astrocytederivedclusterinsuppressesamyloidformationinvivo AT aishekurti astrocytederivedclusterinsuppressesamyloidformationinvivo AT lilliandaughrity astrocytederivedclusterinsuppressesamyloidformationinvivo AT karenrjansenwest astrocytederivedclusterinsuppressesamyloidformationinvivo AT denniswdickson astrocytederivedclusterinsuppressesamyloidformationinvivo AT leonardpetrucelli astrocytederivedclusterinsuppressesamyloidformationinvivo AT guojunbu astrocytederivedclusterinsuppressesamyloidformationinvivo AT chiachenliu astrocytederivedclusterinsuppressesamyloidformationinvivo AT johndfryer astrocytederivedclusterinsuppressesamyloidformationinvivo |
_version_ |
1724412132246683648 |