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Open Access 01-12-2024 | Alzheimer's Disease | Research

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

Authors: Roy Chun-Laam Ng, Min Jian, Oscar Ka-Fai Ma, Ariya Weiman Xiang, Myriam Bunting, Jason Shing-Cheong Kwan, Curtis Wai-Kin Wong, Leung-Wah Yick, Sookja Kim Chung, Karen Siu-Ling Lam, Ian E. Alexander, Aimin Xu, Koon-Ho Chan

Published in: Journal of Neuroinflammation | Issue 1/2024

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 (APN^C39S) into the liver of 5xFAD mice that generated only low-molecular-weight trimeric APN (APN^Tri). Single dose of AAV2/8-APN^C39S in the liver increased circulatory and cerebral APN levels indicating the overexpressed APN^Tri was able to cross the BBB. Overexpression of APN^Tri decreased both the soluble and fibrillar Aβ in the brains of 5xFAD mice. AAV2/8-APN^Tri treatment reduced Aβ-induced IL-1β and IL-18 secretion by suppressing microglial NLRP3-inflammasome activation. The memory functions improved significantly in AAV-APN^Tri-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.

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Title: Liver-specific adiponectin gene therapy suppresses microglial NLRP3-inflammasome activation for treating Alzheimer’s disease
Authors: Roy Chun-Laam Ng
Min Jian
Oscar Ka-Fai Ma
Ariya Weiman Xiang
Myriam Bunting
Jason Shing-Cheong Kwan
Curtis Wai-Kin Wong
Leung-Wah Yick
Sookja Kim Chung
Karen Siu-Ling Lam
Ian E. Alexander
Aimin Xu
Koon-Ho Chan
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Alzheimer's Disease
Alzheimer's Disease
Gene Therapy in Oncology
Published in: Journal of Neuroinflammation / Issue 1/2024
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-024-03066-y

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

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Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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