File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
Supplementary

Article: Liver-specific adiponectin gene therapy suppresses microglial NLRP3-inflammasome activation for treating Alzheimer’s disease

TitleLiver-specific adiponectin gene therapy suppresses microglial NLRP3-inflammasome activation for treating Alzheimer’s disease
Authors
KeywordsAdiponectin
Alzheimer’s Disease
Gene delivery
Neuroinflammation
NLRP3
Issue Date27-Mar-2024
PublisherBioMed Central
Citation
Journal of Neuroinflammation, 2024, v. 21, n. 1 How to Cite?
Abstract

Adiponectin (APN) is an adipokine which predominantly expresses in adipocytes with neuroprotective and anti-inflammatory effects. We have recently indicated that circulatory trimeric APN can enter the brain by crossing the blood–brain barrier (BBB) and modulate microglia-mediated neuroinflammation. Here, we found that the microglial NLR family pyrin domain containing 3 (NLRP3)-inflammasome activation was exacerbated in APN−/−5xFAD mice in age-dependent manner. The focus of this study was to develop a new and tractable therapeutic approach for treating Alzheimer’s disease (AD)-related pathology in 5xFAD mice using peripheral APN gene therapy. We have generated and transduced adeno-associated virus (AAV2/8) expressing the mouse mutated APN gene (APNC39S) into the liver of 5xFAD mice that generated only low-molecular-weight trimeric APN (APNTri). Single dose of AAV2/8-APNC39S in the liver increased circulatory and cerebral APN levels indicating the overexpressed APNTri was able to cross the BBB. Overexpression of APNTri decreased both the soluble and fibrillar Aβ in the brains of 5xFAD mice. AAV2/8-APNTri treatment reduced Aβ-induced IL-1β and IL-18 secretion by suppressing microglial NLRP3-inflammasome activation. The memory functions improved significantly in AAV-APNTri-treated 5xFAD mice with reduction of dystrophic neurites. These findings demonstrate that peripheral gene delivery to overexpress trimeric APN can be a potential therapy for AD.


Persistent Identifierhttp://hdl.handle.net/10722/342164
ISSN
2023 Impact Factor: 9.3
2023 SCImago Journal Rankings: 2.831
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorNg, Roy Chun-Laam-
dc.contributor.authorJian, Min-
dc.contributor.authorMa, Oscar Ka-Fai-
dc.contributor.authorXiang, Ariya Weiman-
dc.contributor.authorBunting, Myriam-
dc.contributor.authorKwan, Jason Shing-Cheong-
dc.contributor.authorWong, Curtis Wai-Kin-
dc.contributor.authorYick, Leung-Wah-
dc.contributor.authorChung, Sookja Kim-
dc.contributor.authorLam, Karen Siu-Ling-
dc.contributor.authorAlexander, Ian E-
dc.contributor.authorXu, Aimin-
dc.contributor.authorChan, Koon-Ho-
dc.date.accessioned2024-04-17T03:49:43Z-
dc.date.available2024-04-17T03:49:43Z-
dc.date.issued2024-03-27-
dc.identifier.citationJournal of Neuroinflammation, 2024, v. 21, n. 1-
dc.identifier.issn1742-2094-
dc.identifier.urihttp://hdl.handle.net/10722/342164-
dc.description.abstract<p>Adiponectin (APN) is an adipokine which predominantly expresses in adipocytes with neuroprotective and anti-inflammatory effects. We have recently indicated that circulatory trimeric APN can enter the brain by crossing the blood–brain barrier (BBB) and modulate microglia-mediated neuroinflammation. Here, we found that the microglial NLR family pyrin domain containing 3 (NLRP3)-inflammasome activation was exacerbated in <em>APN</em><sup><em>−/−</em></sup>5xFAD mice in age-dependent manner. The focus of this study was to develop a new and tractable therapeutic approach for treating Alzheimer’s disease (AD)-related pathology in 5xFAD mice using peripheral APN gene therapy. We have generated and transduced adeno-associated virus (AAV2/8) expressing the mouse mutated <em>APN</em> gene (APN<sup>C39S</sup>) into the liver of 5xFAD mice that generated only low-molecular-weight trimeric APN (APN<sup>Tri</sup>). Single dose of AAV2/8-APN<sup>C39S</sup> in the liver increased circulatory and cerebral APN levels indicating the overexpressed APN<sup>Tri</sup> was able to cross the BBB. Overexpression of APN<sup>Tri</sup> decreased both the soluble and fibrillar Aβ in the brains of 5xFAD mice. AAV2/8-APN<sup>Tri</sup> treatment reduced Aβ-induced IL-1β and IL-18 secretion by suppressing microglial NLRP3-inflammasome activation. The memory functions improved significantly in AAV-APN<sup>Tri</sup>-treated 5xFAD mice with reduction of dystrophic neurites. These findings demonstrate that peripheral gene delivery to overexpress trimeric APN can be a potential therapy for AD.</p>-
dc.languageeng-
dc.publisherBioMed Central-
dc.relation.ispartofJournal of Neuroinflammation-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectAdiponectin-
dc.subjectAlzheimer’s Disease-
dc.subjectGene delivery-
dc.subjectNeuroinflammation-
dc.subjectNLRP3-
dc.titleLiver-specific adiponectin gene therapy suppresses microglial NLRP3-inflammasome activation for treating Alzheimer’s disease-
dc.typeArticle-
dc.identifier.doi10.1186/s12974-024-03066-y-
dc.identifier.scopuseid_2-s2.0-85188920897-
dc.identifier.volume21-
dc.identifier.issue1-
dc.identifier.eissn1742-2094-
dc.identifier.isiWOS:001195134700001-
dc.identifier.issnl1742-2094-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats