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

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 Alexander, Aimin Xu, Koon-Ho Chan

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Article number77
JournalJournal of Neuroinflammation
Volume21
Issue number1
DOIs
Publication statusPublished - 27 Mar 2024

Keywords

  • Adiponectin
  • Alzheimer's Disease
  • Gene Delivery
  • NLRP3
  • Neuroinflammation

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