Chronic oral administration of adipoRon reverses cognitive impairments and ameliorates neuropathology in an Alzheimer's disease mouse model

  • Mol Psychiatry. 2021 Oct;26(10):5669-5689. doi: 10.1038/s41380-020-0701-0.
Roy Chun-Laam Ng  1  2 ,  Min Jian  1  2 ,  Oscar Ka-Fai Ma  1  2 ,  Myriam Bunting  1  2 ,  Jason Shing-Cheong Kwan  1  2 ,  Guang-Jie Zhou  3 ,  Krishnamoorthi Senthilkumar  4 ,  Ashok Iyaswamy  4 ,  Ping-Kei Chan  5 ,  Min Li  4 ,  Kenneth Mei-Yee Leung  3 ,  Siva-Sundara Kumar Durairajan  4  6 ,  Karen Siu-Ling Lam  1  7 ,  Leung-Wing Chu  1 ,  Richard Festenstein  5 ,  Sookja Kim Chung  7  8  9 ,  Koon-Ho Chan  10  11  12
Affiliations
  • 1. Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 2. Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 3. The Swire Institute of Marine Science and School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China.
  • 4. Mr & Mrs Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
  • 5. Gene Control Mechanisms and Disease Group, Department of Brain Sciences, Faculty of Medicine, MRC London Institute of Medical Sciences, Imperial College London, London, W120NN, UK.
  • 6. Division of Myobiology and Neurodegenerative Disease Research, Department of Microbiology, School of Life Sciences, Central University of Tamil Nadu, Tiruvarur, India.
  • 7. Research Center of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Pokfulam, Hong Kong, China.
  • 8. School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 9. Faculty of Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau.
  • 10. Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China. [email protected].
  • 11. Neuroimmunology and Neuroinflammation Research Laboratory, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China. [email protected].
  • 12. Research Center of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Pokfulam, Hong Kong, China. [email protected].
PMID: 32132650 DOI: 10.1038/s41380-020-0701-0
Abstract

Circulating Adiponectin (APN) levels decrease with age and obesity. On the Other hand, a reduction in APN levels is associated with neurodegeneration and neuroinflammation. We previously showed that aged Adiponectin knockout (APN-/-) mice developed Alzheimer's like pathologies, cerebral Insulin resistance, and cognitive impairments. More recently, we also demonstrated that APN deficiency increased Aβ-induced microglia activation and neuroinflammatory responses in 5xFAD mice. There is compelling evidence that deregulated Insulin activities or cerebral Insulin resistance contributes to neuroinflammation and Alzheimer's disease (AD) pathogenesis. Here, we demonstrated that APN levels were reduced in the brain of AD patients and 5xFAD mice. We crossbred 5xFAD mice with APN-/- mice to generate APN-deficient 5xFAD (5xFAD;APN-/-). APN deficiency in 5xFAD mice accelerated amyloid loading, increased cerebral amyloid angiopathy, and reduced insulin-signaling activities. Pharmacokinetics study demonstrated adipoRon (APN receptor agonist) was a blood-brain barrier penetrant. AdipoRon improved neuronal insulin-signaling activities and Insulin sensitivity in vitro and in vivo. Chronic adipoRon treatment improved spatial memory functions and significantly rescued neuronal and synaptic loss in 5xFAD and 5xFAD;APN-/- mice. AdipoRon lowered plaque and Aβ levels in AD mice. AdipoRon also exerted anti-inflammatory effects by reducing microglial and astrocytes activation as well as suppressing cerebral cytokines levels. The microglial phagocytic activity toward Aβ was restored after adipoRon treatment. Our results indicated that adipoRon exerts multiple beneficial effects providing important therapeutic implications. We propose chronic adipoRon administration as a potential treatment for AD.

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