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

Abstract

BackgroundInsulin 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.MethodsTo 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.ResultsAged APN-deficient mice displayed spatial memory and learning impairments, fear-conditioned memory deficit as well as anxiety. These mice also developed AD pathologies including increased cerebral Aβ42 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 synaptic loss in the brain. AD pathologies-associated APN-KO mice displayed attenuated AMPK phosphorylation and impaired insulin signaling including decreased Akt induction and increased GSK3β activation in the hippocampus and frontal cortex. Aged APN-KO mice developed hippocampal insulin resistance with reduced pAkt induction upon intracerebral insulin injection. Consistently, APN treatment in SH-SY5Y cells with insulin resistance and overexpressing Aβ induce higher pAkt levels through AdipoR1 upon insulin treatment whereas the induction was blocked by compound C, indicating APN can enhance neuronal insulin sensitivity through AMPK activation.ConclusionOur results indicated that chronic APN deficiency inactivated AMPK causing insulin desensitization and elicited AD-like pathogenesis in aged mice which also developed significant cognitive impairments and psychiatric symptoms.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0136-x) contains supplementary material, which is available to authorized users.

Importance of adiponectin activity in the pathogenesis of Alzheimer's disease

“…In support of this view, APN ameliorated neuropathological features, such as protein aggregation and impaired motor activity, in a mouse model of α ‐synucleinopathies 7. Osmotin, a plant homologue of APN, attenuates A β 42‐induced neurotoxicity and tau hyperphosphorylation in the hippocampus of wild‐type mice,8 and it was recently shown that aged APN‐knockout mice have characteristics of brain insulin desensitization and development of an AD‐like pathology 32…”

“…However, all studies of APN actions in neurodegenerative diseases have been performed in male mice to exclude the effects of the estrous cycle on behavioral and psychiatric states, including mood, anxiety, learning, and memory 7, 8, 32, 64. Thus, a study is required for comparison of the effects of APN in male and female mice.…”

Potential Neuroprotective Effects of Adiponectin in Alzheimer’s Disease

“…The insulin sensitivity of the insulin resistant SH-SY5Y was restored after treatment with exogenous trimeric adiponectin protein through the activation of AMPK. Our findings provide strong evidence that reduced adiponectin is associated with deregulated cerebral insulin signaling and AD pathogenesis in aged or T2DM subjects who have decreased CNS adiponectin levels [86]. …”

“…These studies only revealed associations or correlations, and showed variation among different study groups. No cause-and-effect study had been conducted until we recently reported that chronic adiponectin deficiency elicited AD-like phenotypes, pathologies and cognitive impairments with cerebral insulin resistance in aged mice [86]. …”

Adiponectin Paradox in Alzheimer's Disease; Relevance to Amyloidogenic Evolvability?

“…Subsequently, osmotin, a plant homolog of APN, was shown to attenuate Aβ42-induced neurotoxicity and tau hyperphosphorylation in the hippocampus in mice brains (21). Moreover, a recent study showed that aged APN-knockout mice had developed characteristics of an ADlike pathology associated with dysregulation of insulin receptor signaling (22).…”