Adiponectin deficiency exacerbated vasculo-neuronal dysfunction and degeneration in Alzheimer’s disease mice model

Abstract

Objectives: The adipocyte-derived hormone, adiponectin (APN), possesses anti-inflammatory and anti-atheroscleorotic effects. Its level decreases with age and has been hypothesized to contribute to brain endothelium dysfunction as well as Alzheimer’s disease (AD) pathogenesis. Methods: To test this hypothesis, we crossbred 5XFAD mice with adiponectin knockout mice. We studied the BBB integrity by morphometric analysis. We also studied the inflammatory responses by ELISA and immunofluorescent analyses. Behavioral tests including Morris water maze, novel object recognition and fear conditioning were performed to assess the memory functions. We also isolated the murine brain microvascular endothelial cells to study the effects of adiponectin signaling in endothelium functions under Ab toxicity. Results: Our results indicated that APN deficiency in 5XFAD mice leads to early cerebral microvascular degeneration with reduction of tight junction molecules, endothelial cells inflammation with drastic increase of IL-1beta and BBB leakage which coincided with the changes in vascular architecture observed. APN deficiency also accelerated deposition of amyloid β-peptide (Aβ) in microvessels without altering Ab load in parenchyma. Behavioral deficits, progressive neuronal loss and neurodegeneration were found after initial cerebrovascular degenerative changes in APN-deficient 5XFAD mice. These vascular and neuronal changes were alleviated by oral administration of adipoRon, an adiponectin receptor agonist. Conclusion: To conclude, chronic APN deficiency worsens AD cerebrovascular degeneration, neuropathology and cognitive function, suggesting that APN may represent a therapeutic target for AD vasculo-neuronal dysfunction and degeneration.