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

Autor: 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.; Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.; Division of Neuroscience, Faculty of Biology, Medicine and Health, School of Biological Sciences, University of Manchester, Manchester, UK., Jian M; 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.; Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Ma OK; 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.; Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China., 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.; Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Bunting M; 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.; 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.; Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Wong CW; 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.; 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.; Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Chung SK; Faculty of Medicine, Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery at Macau University of Science and Technology, Taipa, Macao, 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.; Research Center of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Pokfulam, Hong Kong, China., Alexander IE; Gene Therapy Research Unit, Faculty of Medicine and Health, Children's Medical Research Institute and Sydney Children's Hospitals Network, The University of Sydney, Westmead, NSW, Australia., 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.; Research Center of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Pokfulam, Hong Kong, China., Chan KH; 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. koonho@hku.hk.; Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China. koonho@hku.hk.; Research Center of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Pokfulam, Hong Kong, China. koonho@hku.hk.
Jazyk: angličtina
Zdroj: Journal of neuroinflammation [J Neuroinflammation] 2024 Mar 27; Vol. 21 (1), pp. 77. Date of Electronic Publication: 2024 Mar 27.
DOI: 10.1186/s12974-024-03066-y
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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