New animal models of Alzheimer’s disease that display insulin desensitization in the brain

Gao, Chong; Liu, Yueze; Li, Lin; Hölscher, Christian

doi:10.1515/revneuro-2013-0034

Cited by 27 publications

(23 citation statements)

References 83 publications

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“…This AD animal model also develops insulin desensitization in the brain, caused by STZ injections (Dhull et al, 2012;Lester-Coll et al, 2006;Plaschke, Mueller, & Hoyer, 2010;Salkovic-Petrisic & Hoyer, 2007). STZ enhances tau phosphorylation in the brain and that drugs developed for T2DM have protective effects in this model (Gao, Liu, Jiang, Ding, & Li, 2014;Gao, Liu, Li, & Hoelscher, 2013;Lester-Coll et al, 2006;Li et al, 2012;Shi et al, 2017). We therefore wanted to test whether the novel dual agonist DA5-CH has neuroprotective and restorative properties in the icv.-STZ-treated rat model of AD.…”

Section: Introductionmentioning

confidence: 99%

The novel GLP‐1/GIP analogue DA5‐CH reduces tau phosphorylation and normalizes theta rhythm in the icv. STZ rat model of AD

Cheng

Liu

et al. 2020

Brain and Behavior

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Introduction Alzheimer's disease (AD) is the most common progressive neurodegenerative disease for which there is no cure. Recent studies have shown a close link between type 2 diabetes and AD, which suggested that drugs for type 2 diabetes may be effective for AD. GLP‐1 and GIP are incretin hormones that can ameliorate diabetes. Methods In the present study, we tested the novel dual GLP‐1/GIP receptor agonist DA5‐CH in the icv. streptozotocin (STZ)‐induced insulin desensitization model of AD in rats to explore the protective effects of DA5‐CH. Results The results show that DA5‐CH could reverse the STZ‐induced working memory impairments in a Y‐maze tests, and spatial memory impairments in the water maze task, and decrease the levels of phosphorylated tauS396 protein in the hippocampus. In EEG recordings, STZ treatment diminished the power of the theta band frequency. DA5‐CH was able to increase the energy of theta band activity in the hippocampal CA1 region. The drug also increased the expression of synapse‐related proteins in the hippocampus. After DA5‐CH treatment, mitochondrial stress was alleviated as shown by the improved ratio of Bax/Bcl‐2 in the hippocampus. Growth factor signaling was also normalized as shown by the increased level of the transcription factor P‐CREBS133. In addition, we were able to show that DA5‐CH can cross the blood–brain barrier at an increased rate compared with other dual GLP‐1/GIP or single GLP‐1 receptor agonists. Conclusion Therefore, our results demonstrate that DA5‐CH has neuroprotective effects in the STZ‐induced animal model and that DA5‐CH has potential to treat neurodegenerative disorders such as AD.

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Section: Introductionmentioning

confidence: 99%

The novel GLP‐1/GIP analogue DA5‐CH reduces tau phosphorylation and normalizes theta rhythm in the icv. STZ rat model of AD

Cheng

Liu

et al. 2020

Brain and Behavior

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“…Studies using transgenic AD mice models revealed that the transgenic mice exhibited hippocampal insulin resistance [11]. Leptin-deficient mice, a T2DM model, displayed impaired cerebral insulin signaling and cognitive impairments after treating with high-fat-diet [12, 13]. Postmortem study of AD brains indicated significant increase of insulin receptor substrate-1 (IRS-1) phosphorylation at serine residues, marker of insulin resistance.…”

Section: Introductionmentioning

confidence: 99%

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

Cheng

Jian

et al. 2016

Mol Neurodegeneration

140

137

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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.

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“…Alzheimer's disease involves multifactorial brain changes including problems with amyloid and tau processing, neuronal degeneration, insulin dysregulation, synaptic loss, chronic inflammation, oxidative stress, and accumulation of metals [1][2][3]. The disruption of metal homeostasis has led to the suggested use of metal-binding agents as a potential therapeutic strategy [3].…”

Section: Introductionmentioning

confidence: 99%

Intranasal deferoxamine engages multiple pathways to decrease memory loss in the APP/PS1 model of amyloid accumulation

Fine

Renner

Forsberg

et al. 2015

Neuroscience Letters

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New animal models of Alzheimer’s disease that display insulin desensitization in the brain

Cited by 27 publications

References 83 publications

The novel GLP‐1/GIP analogue DA5‐CH reduces tau phosphorylation and normalizes theta rhythm in the icv. STZ rat model of AD

The novel GLP‐1/GIP analogue DA5‐CH reduces tau phosphorylation and normalizes theta rhythm in the icv. STZ rat model of AD

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

Intranasal deferoxamine engages multiple pathways to decrease memory loss in the APP/PS1 model of amyloid accumulation

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