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

Research output: Journal Publications and ReviewsRGC 21 - Publication in refereed journalpeer-review

46 Scopus Citations
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Author(s)

  • Roy Chun-Laam Ng
  • Min Jian
  • Oscar Ka-Fai Ma
  • Myriam Bunting
  • Jason Shing-Cheong Kwan
  • Guang-Jie Zhou
  • Krishnamoorthi Senthilkumar
  • Ashok Iyaswamy
  • Ping-Kei Chan
  • Min Li
  • Siva-Sundara Kumar Durairajan
  • Karen Siu-Ling Lam
  • Leung-Wing Chu
  • Richard Festenstein
  • Sookja Kim Chung
  • Koon-Ho Chan

Detail(s)

Original languageEnglish
Pages (from-to)5669–5689
Journal / PublicationMolecular Psychiatry
Volume26
Online published4 Mar 2020
Publication statusPublished - Oct 2021
Externally publishedYes

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.

Citation Format(s)

Chronic oral administration of adipoRon reverses cognitive impairments and ameliorates neuropathology in an Alzheimer’s disease mouse model. / Ng, Roy Chun-Laam; Jian, Min; Ma, Oscar Ka-Fai et al.
In: Molecular Psychiatry, Vol. 26, 10.2021, p. 5669–5689.

Research output: Journal Publications and ReviewsRGC 21 - Publication in refereed journalpeer-review