Obesity and Hepatic Steatosis Are Associated with Elevated Serum Amyloid Beta in Metabolically Stressed APPswe/PS1dE9 Mice

Shie, Feng Shiun; Shiao, Young‐Ji; Yeh, Chih Wen; Lin, Chien Hung; Tzeng, Tsai Teng; Hsu, Hao Chieh; Huang, Fong Lee; Tsay, Huey Jen; Liu, Hui Kang

doi:10.1371/journal.pone.0134531

Cited by 21 publications

(23 citation statements)

References 27 publications

(32 reference statements)

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“…Similar results were obtained following induction of diabetes by β‐cell ablation with streptozotocin in conjunction with high‐fat feeding in APP(SWE)/PSEN1dE9 mice . In this study, circulating Aβ levels were significantly correlated with body weight gain, blood glucose and hepatic triglyceride content . Similarly, genetic susceptibility to metabolic disease is exaggerated with elevated amyloidogenic APP processing.…”

Section: An Integrated Model For Metabolic Regulation By App/app Peptsupporting

confidence: 83%

“…For example, APP(SWE)/PSEN1(A246E) mice, comprising an AD mouse model with elevated systemic levels of Aβ, are more susceptible to high‐fat diet‐induced weight gain, hyperglycaemia and glucose intolerance . Similar results were obtained following induction of diabetes by β‐cell ablation with streptozotocin in conjunction with high‐fat feeding in APP(SWE)/PSEN1dE9 mice . In this study, circulating Aβ levels were significantly correlated with body weight gain, blood glucose and hepatic triglyceride content .…”

Section: An Integrated Model For Metabolic Regulation By App/app Peptsupporting

confidence: 76%

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Emerging roles for the amyloid precursor protein and derived peptides in the regulation of cellular and systemic metabolism

Czeczor

McGee

2017

J Neuroendocrinology

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The amyloid precursor protein (APP) is a transmembrane protein that can be cleaved by proteases through two different pathways to yield a number of small peptides, each with distinct physiological properties and functions. It has been extensively studied in the context of Alzheimer`s disease, with the APP-derived amyloid β (Aβ) peptide being a major constituent of the amyloid plaques observed in this disease. It has been known for some time that APP can regulate neuronal metabolism; however, the present review examines the evidence indicating that APP and its peptides can also regulate key metabolic processes such as insulin action, lipid synthesis and storage and mitochondrial function in peripheral tissues. This review presents the hypothesis that amyloidogenic processing of APP in peripheral tissues plays a key role in the response to nutrient excess and that this could contribute to the pathogenesis of metabolic diseases such as obesity and type 2 diabetes (T2D). K E Y W O R D Samyloid β, APP, insulin resistance, mitochondria | INTRODUCTIONThe amyloid precursor protein (APP) has been extensively studied, primarily because it gives rise to the amyloid β (Aβ) peptide, which has been implicated in the pathogenesis of Alzheimer's disease (AD). It is clear that APP, as well as other peptides generated by its cleavage, have biological functions beyond those attributed to Aβ alone. Indeed, loss of function models have established that APP is involved in neuronal development and progenitor cell proliferation and differentiation, synaptic plasticity and specific cellular signalling processes.1 A growing body of evidence suggests that APP and its cleaved peptides also regulate a variety of metabolic processes. | APP STRUCTURE, EXPRESSION AND APP PROCESSINGBased on homology, APP belongs to a family of proteins that in mammals also includes the APP like proteins (APLP) 1 and 2. 4 The present review primarily focuses on APP; however, there is considerable functional overlap between these proteins. 4 These transmembrane proteins all have a large extracellular region and a smaller cytoplasmic region, which are linked by a single pass transmembrane domain. 5These domains can be cleaved by a number of different proteases to yield a number of distinct peptides. Interestingly, APP is the only APP family member to contain the domain that encodes the Aβ peptide. 6Although all APP family members are highly expressed in neurones,

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Section: An Integrated Model For Metabolic Regulation By App/app Peptsupporting

confidence: 83%

Section: An Integrated Model For Metabolic Regulation By App/app Peptsupporting

confidence: 76%

Emerging roles for the amyloid precursor protein and derived peptides in the regulation of cellular and systemic metabolism

Czeczor

McGee

2017

J Neuroendocrinology

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“…Diet-induced peripheral metabolic changes have been suggested to be linked with amyloidosis [ 18 ]. Previously, we created an HFSTZ APP/PS1 animal model, which displayed diabesity and hepatic steatosis; elevated peripheral Aβ level; enhanced Aβ level, plaque burden, astrocyte activation, vascular inflammation, glucose hypometabolism in the cerebrum, and caused cognitive impairment in APP/PS1 mice [ 3 , 4 ]. In the present study, the effects of APS on the pathological changes stated above were studied.…”

Section: Discussionmentioning

confidence: 99%

“…In our previous studies, we found that obesity, hyperglycemia, hepatic steatosis, Aβ plaque burdens and cerebrovascular inflammation in APPswe/PS1ΔE9 (APP/PS1) transgenic mice is accelerated by the combination of high-fat diet (HFD) and a low-dose injection of streptozotocin (STZ) (i.e., HFSTZ AD mice) [ 3 , 4 , 5 ]. In those studies, we found an interplay between genetic background of AD and HFSTZ-induced metabolic stress.…”

Section: Introductionmentioning

confidence: 99%

Astragalus membranaceus-Polysaccharides Ameliorates Obesity, Hepatic Steatosis, Neuroinflammation and Cognition Impairment without Affecting Amyloid Deposition in Metabolically Stressed APPswe/PS1dE9 Mice

Huang

Tsay²,

et al. 2017

IJMS

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Astragalus membranaceus is commonly used in traditional Chinese medicine for strengthening the host defense system. Astragalus membranaceus-polysaccharides is an effective component with various important bioactivities, such as immunomodulation, antioxidant, anti-diabetes, anti-inflammation and neuroprotection. In the present study, we determine the effects of Astragalus membranaceus-polysaccharides on metabolically stressed transgenic mice in order to develop this macromolecules for treatment of sporadic Alzheimer’s disease, a neurodegenerative disease with metabolic risk factors. Transgenic mice, at 10 weeks old prior to the appearance of senile plaques, were treated in combination of administrating high-fat diet and injecting low-dose streptozotocin to create the metabolically stressed mice model. Astragalus membranaceus-polysaccharides was administrated starting at 14 weeks for 7 weeks. We found that Astragalus membranaceus-polysaccharides reduced metabolic stress-induced increase of body weight, insulin and insulin and leptin level, insulin resistance, and hepatic triglyceride. Astragalus membranaceus-polysaccharides also ameliorated metabolic stress-exacerbated oral glucose intolerance, although the fasting blood glucose was only temporally reduced. In brain, metabolic stress-elicited astrogliosis and microglia activation in the vicinity of plaques was also diminished by Astragalus membranaceus-polysaccharides administration. The plaque deposition, however, was not significantly affected by Astragalus membranaceus-polysaccharides administration. These findings suggest that Astragalus membranaceus-polysaccharides may be used to ameliorate metabolic stress-induced diabesity and the subsequent neuroinflammation, which improved the behavior performance in metabolically stressed transgenic mice.

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“…Interestingly, a number of AD animal models with increased circulating Aβ levels are reported to recapitulate aspects of the metabolic disturbances seen in obesity and type 2 diabetes. These include insulin resistance, glucose tolerance and dyslipidaemia (Mody et al 2011, Jimenez-Palomares et al 2012, Shie et al 2015, Plucinska et al 2016. Administration of the Aβ 42 peptide to mice has similar effects by inducing hepatic insulin resistance (Zhang et al 2012(Zhang et al , 2013.…”

Section: Introductionmentioning

confidence: 99%

APP deficiency results in resistance to obesity but impairs glucose tolerance upon high fat feeding

Czeczor

Genders

Aston-Mourney

et al. 2018

Journal of Endocrinology

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The amyloid precursor protein (APP) generates a number of peptides when processed through different cleavage mechanisms, including the amyloid beta peptide that is implicated in the development of Alzheimer's disease. It is well established that APP via its cleaved peptides regulates aspects of neuronal metabolism. Emerging evidence suggests that amyloidogenic processing of APP can lead to altered systemic metabolism, similar to that observed in metabolic disease states. In the present study, we investigated the effect of APP deficiency on obesity-induced alterations in systemic metabolism. Compared with WT littermates, APP-deficient mice were resistant to diet-induced obesity, which was linked to higher energy expenditure and lipid oxidation throughout the dark phase and was associated with increased spontaneous physical activity. Consistent with this lean phenotype, APP-deficient mice fed a high-fat diet (HFD) had normal insulin tolerance. However, despite normal insulin action, these mice were glucose intolerant, similar to WT mice fed a HFD. This was associated with reduced plasma insulin in the early phase of the glucose tolerance test. Analysis of the pancreas showed that APP was required to maintain normal islet and β-cell mass under high fat feeding conditions. These studies show that, in addition to regulating aspects of neuronal metabolism, APP is an important regulator of whole body energy expenditure and glucose homeostasis under high fat feeding conditions.

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Obesity and Hepatic Steatosis Are Associated with Elevated Serum Amyloid Beta in Metabolically Stressed APPswe/PS1dE9 Mice

Cited by 21 publications

References 27 publications

Emerging roles for the amyloid precursor protein and derived peptides in the regulation of cellular and systemic metabolism

Emerging roles for the amyloid precursor protein and derived peptides in the regulation of cellular and systemic metabolism

Astragalus membranaceus-Polysaccharides Ameliorates Obesity, Hepatic Steatosis, Neuroinflammation and Cognition Impairment without Affecting Amyloid Deposition in Metabolically Stressed APPswe/PS1dE9 Mice

APP deficiency results in resistance to obesity but impairs glucose tolerance upon high fat feeding

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