An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease–associated Aβ oligomers

Bomfim, Theresa R.; Forny-Germano, Letícia; Sathler, Luciana B.; Brito-Moreira, Jordano; Houzel, Jean-Christophe; Decker, Helena; Silverman, Michael; Kazi, Hala; Melo, Helen M.; McClean, Paula; Hölscher, Christian; Arnold, Steven E.; Talbot, Konrad; Klein, William L.; Munoz, Douglas P.; Ferreira, Sérgio T.; Felice, Fernanda G. De

doi:10.1172/jci57256

Cited by 741 publications

(720 citation statements)

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“…Similarly, treatment of patients with type 2 diabetes and islet recipients with type 1 diabetes, at early stages of beta cell dysfunction may slow down the process of hIAPP aggregation and thereby amyloid-induced beta cell death. In support, two recent studies have demonstrated that treatment with GLP-1R agonists, such as exenatide and liraglutide, reduces Aβ oligomers, amyloid plaque formation and toxicity in the brains of mice in models of Alzheimer's disease [47,48].…”

Section: Discussionmentioning

confidence: 77%

“…We further demonstrated that exenatide-treated islets had markedly lower levels of beta cell phospho-JNK, suggesting that exenatide may protect islet beta cells from amyloid toxicity by reducing JNK activation. Interestingly, elevated JNK phosphorylation and prevention of its activation by exenatide were recently reported in a mouse model of Alzheimer's disease [48], raising the idea that different forms of amyloidogenesis share similar mechanisms of toxicity.…”

Section: Discussionmentioning

confidence: 98%

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The glucagon-like peptide-1 receptor agonist exenatide restores impaired pro-islet amyloid polypeptide processing in cultured human islets: implications in type 2 diabetes and islet transplantation

Park

Kieffer

et al. 2012

Diabetologia

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Aims/hypothesis Islet amyloid, formed by aggregation of human islet amyloid polypeptide (hIAPP), is associated with beta cell death in type 2 diabetes as well as in cultured and transplanted human islets. Impaired prohIAPP processing due to beta cell dysfunction is implicated in hIAPP aggregation. We examined whether the glucagon-like peptide-1 receptor (GLP-1R) agonist exenatide can restore impaired prohIAPP processing and reduce hIAPP aggregation in cultured human islets and preserve beta cell function/mass during culture conditions used in clinical islet transplantation. Methods Isolated human islets (n010 donors) were cultured with or without exenatide in normal or elevated glucose for 2 or 7 days. Beta cell apoptosis, proliferation, mass, function, cJUN N-terminal kinase (JNK) and protein kinase B (PKB) activation and amyloid formation were assessed. ProhIAPP, its intermediates and mature hIAPP were detected. Results Exenatide-treated islets had markedly lower JNK and caspase-3 activation and beta cell apoptosis, resulting in higher beta/alpha cell ratio and beta cell area than nontreated cultured islets. Exenatide improved beta cell function, manifested as higher insulin response to glucose and insulin content, compared with non-treated cultured islets. Phospho-PKB immunoreactivity was detectable in exenatide-treated but not untreated cultured islets. Islet culture caused impaired prohIAPP processing with decreased mature hIAPP and increased NH 2 -terminally unprocessed prohIAPP levels resulting in higher release of immature hIAPP. Exenatide restored prohIAPP processing and reduced hIAPP aggregation in cultured islets. Conclusions/interpretation Exenatide treatment enhances survival and function of cultured human islets and restores impaired prohIAPP processing in normal and elevated glucose conditions thereby reducing hIAPP aggregation. GLP-1R agonists may preserve beta cells in conditions associated with islet amyloid formation.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 98%

The glucagon-like peptide-1 receptor agonist exenatide restores impaired pro-islet amyloid polypeptide processing in cultured human islets: implications in type 2 diabetes and islet transplantation

Park

Kieffer

et al. 2012

Diabetologia

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“…There is a strong link between diabetes, insulin resistance in the brain, and AD (24)(25)(26)(27). Loss of insulin action in the brain also causes increased phosphorylation of tau protein, an early marker of AD (26).…”

Section: Discussionmentioning

confidence: 99%

Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism

Ferris

Perry

Moreira

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

170

117

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Cholesterol is important for normal brain function. The brain synthesizes its own cholesterol, presumably in astrocytes. We have previously shown that diabetes results in decreased brain cholesterol synthesis by a reduction in sterol regulatory elementbinding protein 2 (SREBP2)-regulated transcription. Here we show that coculture of control astrocytes with neurons enhances neurite outgrowth, and this is reduced with SREBP2 knockdown astrocytes. In vivo, mice with knockout of SREBP2 in astrocytes have impaired brain development and behavioral and motor defects. These mice also have altered energy balance, altered body composition, and a shift in metabolism toward carbohydrate oxidation driven by increased glucose oxidation by the brain. Thus, SREBP2-mediated cholesterol synthesis in astrocytes plays an important role in brain and neuronal development and function, and altered brain cholesterol synthesis may contribute to the interaction between metabolic diseases, such as diabetes and altered brain function.T he brain is one of the most cholesterol-rich organs in the body, with cholesterol playing an important role in membrane fluidity, vesicle formation, and synaptogenesis (1). Cholesterol levels are tightly controlled by sterol regulatory element-binding protein 2 (SREBP2), the major transcription factor regulating cholesterol synthetic genes (2). In contrast to fatty acids, which are in equilibrium with the rest of the body, nearly all brain cholesterol is synthesized in the brain because cholesterol-carrying lipoproteins, with the exception of some very dense HDL, cannot readily cross the blood-brain barrier (3-5).When cholesterol is abundant, SREBP2 precursor remains sequestered in the endoplasmic reticulum by SREBP cleavage activating protein (SCAP). As cholesterol is needed, SCAP shuttles SREBP2 to the Golgi for cleavage into a transcriptionally active form that translocates to the nucleus, binds to sterol regulatory elements in DNA, and activates transcription of enzymes of cholesterol synthesis (2). Insulin can regulate SREBP2 expression and activity, in part via two insulin-induced regulatory proteins, Insig1 and Insig2 (6, 7). Furthermore, in insulindeficient diabetes, there is a decrease in SREBP2 and SCAP in the brain leading to decreased brain cholesterol synthesis (8). We have previously shown that both neurons and glial cells express SREBP2 and the enzymes of cholesterol synthesis, and in both cell types expression of the cholesterol synthesis pathway is stimulated by insulin (7).Among the subtypes of glia, astrocytes serve the most diverse roles, providing both structural support to neurons and playing a major role in maintaining the blood-brain barrier. In addition, astrocytes provide a variety of metabolic functions, including storage of glycogen and uptake of ions and neurotransmitters from the synaptic cleft (9, 10).Astrocytes/glial cells have also been suggested to play an important role in brain cholesterol metabolism. When neuronallike retinal ganglion cells are grown in culture and expose...

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“…This pathological change is likely to emerge before Aβ42 accumulation (Chua et al ., 2011). In agreement with previous findings in animal models and patients (Bomfim et al ., 2012; Talbot et al ., 2012), significantly reduced brain expression of IRβ and AKT and increased level of inactive IRS1 (IRS1 pS636 and IRS1 pS612) were found in the APP/PS1 mice used here. This indicates that the brain insulin signaling pathway is already compromised in 6‐month‐old APP/PS1 mice.…”

Section: Discussionmentioning

confidence: 99%

“…Serine phosphorylation in IRS1 (IRS1pSer) has been found in the brain of the APP/PS1 transgenic mouse model and in hippocampi of cynomolgus monkeys receiving i.c.v. injections of Aβ oligomers (Bomfim et al ., 2012). Inhibitory IRS1pSer can block downstream insulin signaling (Zhao et al ., 2008b).…”

Section: Discussionmentioning

confidence: 99%

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

et al. 2016

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SummaryBrain insulin signaling deficits contribute to multiple pathological features of Alzheimer's disease (AD). Although intranasal insulin has shown efficacy in patients with AD, the underlying mechanisms remain largely unillustrated. Here, we demonstrate that intranasal insulin improves cognitive deficits, ameliorates defective brain insulin signaling, and strongly reduces β‐amyloid (Aβ) production and plaque formation after 6 weeks of treatment in 4.5‐month‐old APPswe/PS1dE9 (APP/PS1) mice. Furthermore, c‐Jun N‐terminal kinase activation, which plays a pivotal role in insulin resistance and AD pathologies, is significantly inhibited. The alleviation of amyloid pathology by intranasal insulin results mainly from enhanced nonamyloidogenic processing and compromised amyloidogenic processing of amyloid precursor protein (APP), and from a reduction in apolipoprotein E protein which is involved in Aβ metabolism. In addition, intranasal insulin effectively promotes hippocampal neurogenesis in APP/PS1 mice. This study, exploring the mechanisms underlying the beneficial effects of intranasal insulin on Aβ pathologies in vivo for the first time, highlights important preclinical evidence that intranasal insulin is potentially an effective therapeutic method for the prevention and treatment of AD.

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An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease–associated Aβ oligomers

Abstract: Defective brain insulin signaling has been suggested to contribute to the cognitive deficits in patients with

Cited by 741 publications

References 77 publications

The glucagon-like peptide-1 receptor agonist exenatide restores impaired pro-islet amyloid polypeptide processing in cultured human islets: implications in type 2 diabetes and islet transplantation

The glucagon-like peptide-1 receptor agonist exenatide restores impaired pro-islet amyloid polypeptide processing in cultured human islets: implications in type 2 diabetes and islet transplantation

Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

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