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Liver-specific adiponectin gene therapy suppresses microglial NLRP3-inflammasome activation for treating Alzheimer's disease.
Ng, Roy Chun-Laam; Jian, Min; Ma, Oscar Ka-Fai; Xiang, Ariya Weiman; Bunting, Myriam; Kwan, Jason Shing-Cheong; Wong, Curtis Wai-Kin; Yick, Leung-Wah; Chung, Sookja Kim; Lam, Karen Siu-Ling; Alexander, Ian E; Xu, Aimin; Chan, Koon-Ho.
Afiliação
  • Ng RC; Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, 4/F, Professorial Block, 102 Pokfulam Road, Hong Kong, Special Administrative Region, China.
  • Jian M; Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Ma OK; Division of Neuroscience, Faculty of Biology, Medicine and Health, School of Biological Sciences, University of Manchester, Manchester, UK.
  • Xiang AW; Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, 4/F, Professorial Block, 102 Pokfulam Road, Hong Kong, Special Administrative Region, China.
  • Bunting M; Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Kwan JS; Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, 4/F, Professorial Block, 102 Pokfulam Road, Hong Kong, Special Administrative Region, China.
  • Wong CW; Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Yick LW; Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, 4/F, Professorial Block, 102 Pokfulam Road, Hong Kong, Special Administrative Region, China.
  • Chung SK; Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Lam KS; Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, 4/F, Professorial Block, 102 Pokfulam Road, Hong Kong, Special Administrative Region, China.
  • Alexander IE; Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • Xu A; Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, 4/F, Professorial Block, 102 Pokfulam Road, Hong Kong, Special Administrative Region, China.
  • Chan KH; Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
J Neuroinflammation ; 21(1): 77, 2024 Mar 27.
Article em En | MEDLINE | ID: mdl-38539253
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 Aß in the brains of 5xFAD mice. AAV2/8-APNTri treatment reduced Aß-induced IL-1ß 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Alzheimer Limite: Animals Idioma: En Revista: J Neuroinflammation Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Alzheimer Limite: Animals Idioma: En Revista: J Neuroinflammation Ano de publicação: 2024 Tipo de documento: Article