Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative disease, characterized by excessive beta amyloid (Aβ) deposition in brain, leading to blood–brain barrier (BBB) disruption. The mechanisms of BBB disruption in AD are still unclear, despite considerable research. The adipokine adiponectin is known to regulate various metabolic functions and reduce inflammation. Though adiponectin receptors have been reported in the brain, its role in the central nervous system has not been fully characterized. In the present study, we investigate whether adiponectin contributes to the tight junction integrity and cell death of brain endothelial cells under Aβ-induced toxicity conditions. We measured the expression of adiponectin receptors (AdipoR1 and AdipoR2) and the alteration of tight junction proteins in in vivo 5xFAD mouse brain. Moreover, we examined the production of reactive oxygen species (ROS) and the loss of tight junction proteins such as Claudin 5, ZO-1, and inflammatory signaling in in vitro brain endothelial cells (bEnd.3 cells) under Aβ toxicity. Our results showed that Acrp30 (a globular form of adiponectin) reduces the expression of proinflammatory cytokines and the expression of RAGE as Aβ transporters into brain. Moreover, we found that Acrp 30 attenuated the apoptosis and the tight junction disruption through AdipoR1-mediated NF-κB pathway in Aβ-exposed bEnd.3 cells. Thus, we suggest that adiponectin is an attractive therapeutic target for treating BBB breakdown in AD brain.
Highlights
(Aβ) peptides generated from amyloid precursor protein (APP).[1,2,3] The excessive accumulation of these plaques in the brain impairs synaptic function and leads to neuronal death, manifesting in memory dysfunction.[1,4] Aβ has been known to trigger a synaptopathy of reactive oxygen species (ROS) production, neuronal cell death, glia activation, and tau hyperphosphorylation.[5]
Adiponectin acts by binding with specific receptor AdipoR1 and AdipoR2,21 which exist in various organs including brain.[23,24]
Considering that our results showed the AdipoR1 and AdipoR2 detected cells were neuronal cells in brain, we assume that the adiponectin receptors could be involved in the excitability of neurons[35] and the suppression of neuronal damage against oxidative stress.[36]
Summary
(Aβ) peptides generated from amyloid precursor protein (APP).[1,2,3] The excessive accumulation of these plaques in the brain impairs synaptic function and leads to neuronal death, manifesting in memory dysfunction.[1,4] Aβ has been known to trigger a synaptopathy of reactive oxygen species (ROS) production, neuronal cell death, glia activation, and tau hyperphosphorylation.[5]. Adiponectin is a 244 amino acid polypeptide adipokine encoded by the ADIPOQ gene.[20] It binds to two receptors (AdipoR1 and AdipoR2),[21,22] which exist in the brain as well as other organs throughout the body.[23,24] Adiponectin is known to play key roles as an insulin sensitizer and an anti-inflammatory regulator, in addition to the regulation of glucose metabolism and fatty acid breakdown.[25,26] In the central nervous system, previous reports suggest that adiponectin modulates memory function and has a protective effect on neurons and neural stem cells against stress condition.[27,28] One study showed that serum adiponectin levels were lower in APP transgenic mice compared with control mice and outlined an association with inflammation and cognitive dysfunction in AD.[29] adiponectin reduces the secretion of interleukin-6 (IL-6). Our findings suggest that adiponectin may protect BBB disruption in the AD
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