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

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 (APNC39S) into the liver of 5xFAD mice that generated only low-molecular-weight trimeric APN (APNTri). Single dose of AAV2/8-APNC39S in the liver increased circulatory and cerebral APN levels indicating the overexpressed APNTri was able to cross the BBB. Overexpression of APNTri decreased both the soluble and fibrillar Aß in the brains of 5xFAD mice. AAV2/8-APNTri treatment reduced Aß-induced IL-1ß and IL-18 secretion by suppressing microglial NLRP3-inflammasome activation. The memory functions improved significantly in AAV-APNTri-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.

Identification of a novel adiponectin receptor and opioid receptor dual acting agonist as a potential treatment for diabetic neuropathy.

Diabetic neuropathy (DN) is a long-term complication of diabetes mellitus, affecting different periphery nerve systems including sensory and motor neurons. Hyperglycemia is the major cause of DN with symptoms such as weakness of balance or coordination, insensitivity to sensation, weakness of the muscles as well as numbness and pain in limbs Analgesic drug such as opioids can be effective to relief neuropathy pain but there is no effective treatment. Adiponectin is an anti-diabetic adipokine, which possesses insulin-sensitizing and neuroprotective effects. In this project, we aim to identify an agent which is dual acting to opioid and adiponectin receptors. Within a virtual screening repositioning campaign, a large collection of compounds with different structures comprehensive of adipoRon-like piperidine derivatives was screened by docking. Recently developed opioid receptor benzomorphanic agonists finally emerged as good ligands to adiponectin receptors showing some 2D and 3D structural similarities with AdipoRon. Particularly, we have identified (+)-MML1017, which has high affinity to the same binding domain of AdipoR1 and AdipoR2 as AdipoRon. Our western blot results indicate (+)-MML1017 activates AMPK phosphorylation through both adipoR1 and adipoR2 in neuronal cell line. Moreover, pretreatment of (+)-MML1017 can improve the cell viability with motor neurons under hyperglycermic conditions. The (+)-MML1017 also activates µ-opioid receptor cells in a concentration-dependent manner. Our study identified a novel compound having dual activity on opioid receptors and adiponectin receptors that may have analgesic effects and neuroprotective effects to treat diabetic neuropathy.