Liver-specific adeno-associated virus 2/8 trimer adiponectin gene transfer reduces beta-amyloidosis and improves learning and memory in a mouse model of Alzheimer's disease

Abstract

Objective: Type 2 diabetes is a major risk factor of Alzheimer’s disease (AD). Insulin resistance and inflammation are involved in the pathogenesis of both conditions. Adiponectin, an adipocyte-derived circulating adipokine, possesses anti-inflammatory and insulin-sensitising functions. We have reported that chronic adiponectin deficiency in aged mice developed AD-like pathologies and cognitive impairments. Here, we investigate whether overexpressing trimeric adiponectin by adeno-associated virus (AAV) delivery can reduce AD pathologies by reducing amyloid beta (Aβ) deposition and suppressing neuroinflammation. Methods: To test this hypothesis, transgenic mice (5xFAD) that carried familial APP and PS mutations were given with liver-specific AAV carrying trimeric adiponectin expression plasmid (AAV-APNTri) by intravenous injection. Cognitive functions of these mice were evaluated by Morris water maze 4 months after injection. Enzymelinked immunosorbent assay (ELISA) was performed to study the levels of Aβ peptides and cytokines in the mice brains. Western blotting and immunohistochemistry analysis were performed on brain and tissue cells. Microgliosis and cytokines levels were studied by ELISA and immunofluorescent staining. Results: We demonstrated that liver-specific AAV overexpressed trimeric adiponectin found in the circulation. Spatial learning and memory function were significantly improved in AAV-APNTri-treated 5xFAD mice. Molecular studies indicated overexpressing trimeric adiponectin reduced Aβ40 and Aβ42 levels, Aβ-plaque loading, microgliosis, and astrogliosis. Neuroinflammatory response was also reduced as shown by reduction of proinflammatory cytokine levels. Conclusion: Taken together, these results suggest overexpressing adiponectin is protective against Aβ deposition and neuroinflammation. Trimeric adiponectin exerts anti-inflammatory effects to the AD brains by suppressing microglial activation and proinflammatory cytokine secretion. We suggested that overexpressing trimeric adiponectin by liver-specific AAV delivery can be a potential treatment for AD.