Chronic adiponectin deficiency leads to Alzheimer’s disease-like cognitive impairments and pathologies through AMPK inactivation and cerebral insulin resistance in aged mice

作者：Roy Chun-Laam Ng, On-Yin Cheng, Min Jian, Jason Shing-Cheong Kwan, Philip Wing‐Lok Ho, Kenneth K.Y. Cheng, Patrick Ka Kit Yeung, Lena Zhou, Ruby L.C. Hoo, Sookja Kim Chung, Aimin Xu, Karen S.L. Lam, Koon Ho Chan · 发表于：Molecular Neurodegeneration · 年份：2016 · DOI：10.1186/s13024-016-0136-x · 被引用次数：187 · 研究领域：Adipokines, Inflammation, and Metabolic Diseases、Alzheimer's disease research and treatments、GDF15 and Related Biomarkers

BACKGROUND: Insulin resistance is the major pathogenesis underlying type 2 diabetes mellitus (T2DM) and these patients have doubled risk of Alzheimer's disease (AD). Increasing evidence suggests that insulin resistance plays an important role in AD pathogenesis, possibly due to abnormal GSK3β activation, causing intra- and extracellular amyloid-beta (Aβ) accumulation. Adiponectin (APN) is an adipokine with insulin-sensitizing and anti-inflammatory effects. Reduced circulatory APN level is associated with insulin resistance and T2DM. The role of APN in AD has not been elucidated. In this study, we aim to examine if adiponectin deficiency would lead to cerebral insulin resistance, cognitive decline and Alzheimer's-like pathology in mice. METHODS: To study the role of adiponectin in cognitive functions, we employed adiponectin-knockout (APN-KO) mice and demonstrated chronic APN deficiency in their CNS. Behavioral tests were performed to study the cognitions of male APN-KO mice. Brains and tissue lysates were collected to study the pathophysiological and molecular changes in the brain of APN-KO mice. SH-SY5Y neuroblastoma cell line was used to study the molecular mechanism upon APN and insulin treatment. RESULTS: level, Aβ deposition, hyperphosphorylated Tau proteins, microgliosis and astrogliosis with increased cerebral IL-1β and TNFα levels that associated with increased neuronal apoptosis and reduced synaptic proteins levels, suggesting APN deficiency may lead to neuronal and ...