Is Alzheimer's disease related to metabolic syndrome? A Wnt signaling conundrum

Ríos, Juvenal A.; Cisternas, Pedro; Arrese, Marco; Barja, Salesa; Inestrosa, Nibaldo C.

doi:10.1016/j.pneurobio.2014.07.004

Cited by 90 publications

(68 citation statements)

References 393 publications

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“…1B). Furthermore, we determined if rWnt3a treatment changed the expression of two important metabolic sensors in neurons, AMPK and Akt (4,28,29). We did not observe changes in the expression of p-AMPK-Thr 172 (an activating phosphorylation) after rWnt3a treatment (Fig.…”

Section: Effects Of the Acute Wnt3amentioning

confidence: 87%

“…The involvement of Wnt signaling in the regulation of glucose metabolism has regained importance in recent years, due to studies in humans in which several components of the Wnt pathway have been identified as risk factors for metabolic diseases, including diabetes mellitus type II and age-related dementia; however, the ultimate effect depends on whether the canonical or non-canonical Wnt pathway is affected (4,14,(53)(54)(55). Furthermore, activation of the Wnt/␤-catenin pathway in vivo promotes a decrease in the plasma glucose level, which modulates the localization and expression of GLUT4 in adipocytes and increases glucose uptake in these cells (56).…”

Section: Wnt Signaling Stimulates Glucose Utilization In Neuronsmentioning

confidence: 99%

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Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

Cisternas

Salazar

Silva-Álvarez

et al. 2016

Journal of Biological Chemistry

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Edited by Jeffrey E. PessinThe Wnt signaling pathway is critical for a number of functions in the central nervous system, including regulation of the synaptic cleft structure and neuroprotection against injury. Deregulation of Wnt signaling has been associated with several brain pathologies, including Alzheimer's disease. In recent years, it has been suggested that the Wnt pathway might act as a central integrator of metabolic signals from peripheral organs to the brain, which would represent a new role for Wnt signaling in cell metabolism. Energy metabolism is critical for normal neuronal function, which mainly depends on glucose utilization. Brain energy metabolism is important in almost all neurological disorders, to which a decrease in the capacity of the brain to utilize glucose has been linked. However, little is known about the relationship between Wnt signaling and neuronal glucose metabolism in the cellular context. In the present study, we found that acute treatment with the Wnt3a ligand induced a large increase in glucose uptake, without changes in the expression or localization of glucose transporter type 3. In addition, we observed that Wnt3a treatment increased the activation of the metabolic sensor Akt. Moreover, we observed an increase in the activity of hexokinase and in the glycolytic rate, and both processes were dependent on activation of the Akt pathway. Furthermore, we did not observe changes in the activity of glucose-6-phosphate dehydrogenase or in the pentose phosphate pathway. The effect of Wnt3a was independent of both the transcription of Wnt target genes and synaptic effects of Wnt3a. Together, our results suggest that Wnt signaling stimulates glucose utilization in cortical neurons through glycolysis to satisfy the high energy demand of these cells.

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Section: Effects Of the Acute Wnt3amentioning

confidence: 87%

Section: Wnt Signaling Stimulates Glucose Utilization In Neuronsmentioning

confidence: 99%

Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

Cisternas

Salazar

Silva-Álvarez

et al. 2016

Journal of Biological Chemistry

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“…Alzheimer's disease (AD) is a major source of morbidity and mortality for millions of people worldwide, and intense investigation has led to multiple etiological constructs contributing to AD [1][2][3][4][5][6][7][8][9][10][11][12]. In addition to the recently reviewed, original 'amyloid cascade hypothesis' [1], the development and progression of AD have been associated with viral infection [2], vascular damage from pulse pressure [3], regional deposition of metals, such as iron, resulting in oxidant injury [4][5][6][7][8], metabolic syndrome and morbid obesity [8][9][10], and long term exposure to spontaneous cerebral microemboli [11,12].…”

Section: Introductionmentioning

confidence: 99%

“…In addition to the recently reviewed, original 'amyloid cascade hypothesis' [1], the development and progression of AD have been associated with viral infection [2], vascular damage from pulse pressure [3], regional deposition of metals, such as iron, resulting in oxidant injury [4][5][6][7][8], metabolic syndrome and morbid obesity [8][9][10], and long term exposure to spontaneous cerebral microemboli [11,12]. Of these various paradigms, the notion that spontaneous emboli, most likely due to systemic hypercoagulability, is of particular interest.…”

Section: Introductionmentioning

confidence: 99%

Carbon Monoxide and Iron Modulate Plasmatic Coagulation in Alzheimer’s disease

Nielsen¹,

Pretorius

Bester

et al. 2015

CNR

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Alzheimer's disease (AD) is a significant source of morbidity and mortality for millions of people worldwide, and multiple potential etiologies have been postulated to contribute to AD. Among these, spontaneous cerebral emboli and increased cerebral and circulating heme oxygenase (Hmox) activity in AD patients are of particular interest, as two of the products of Hmox activity, carbon monoxide (CO) and iron enhance plasmatic coagulation and modify the ultrastructure of thrombi. We hypothesized that patients afflicted with AD would have coagulation kinetics modulated by CO and iron. Using viscoelastic assessments of coagulation, it was determined with a small cohort (n=11) of AD patients that all had enhancement of coagulation by CO, iron, or both. In a complementary fashion, it was determined that a separate cohort (n=12) of AD patients had thrombi with ultrastructural features consistent with iron and CO exposure as assessed with scanning electron microscopy. Further, when stratified by normal or abnormally increased serum ferritin concentrations (which can be increased by Hmox), the AD patients with abnormal ferritin concentrations had significantly thinner fibrin fiber diameters, not unlike that noted when normal plasma is mixed with iron or CO. In sum, AD patients were noted to have plasmatic coagulation kinetic and thrombus ultrastructural changes consistent with exposure to CO and iron. Future investigation of CO and iron in the pathogenesis of Alzheimer's disease is warranted.

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“…Understanding and resolving the reasons for these translational failures in AD is therefore imperative. Additionally, several lines of evidence indicate that AD should be reinterpreted as part of a constellation of diseases, in particular, as a complex systemic/metabolic dysfunction, given the significant correlations found between AD and the metabolic syndrome [8], as well as hypometabolism, oxidative stress, and glucose-fatty acid cycle modifications [9]. Consequently, current and past research failures might also be attributed to the fact that traditional research efforts and strategies have not been taking this complexity into account.…”

Section: Introductionmentioning

confidence: 99%

A Human-Based Integrated Framework forAlzheimer’s Disease Research

Pistollato

Cavanaugh

Chandrasekera

2015

JAD

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Abstract. Animal models of Alzheimer's disease (AD) have been extensively utilized for decades in an effort to elucidate the pathophysiological mechanisms of this disease and to test novel therapeutic approaches. However, research success has not effectively translated into therapeutic success for human patients. This translational failure is partially due to the overuse of animal models that cannot accurately recapitulate human AD etiopathogenesis or drug responses and the inadequate use of human-relevant research methods. Here, we propose how to mitigate this translational barrier by employing human-based methods to elucidate disease processes occurring at multiple levels of complexity, accounting for gene and protein expression and the impact of disease at the cellular, tissue/organ, individual, and population levels. In particular, novel human-based cellular and computational models, together with epidemiological and clinical studies, represent the ideal tools to facilitate human-relevant data acquisition, in the effort to better elucidate AD pathogenesis in a human-based setting and design more effective treatments and preventive strategies. Our analysis indicates that a paradigm shift toward human-based, rather than animal-based research is required in the face of the ever-increasing prevalence of AD in the 21st century.

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Is Alzheimer's disease related to metabolic syndrome? A Wnt signaling conundrum

Cited by 90 publications

References 393 publications

Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

Carbon Monoxide and Iron Modulate Plasmatic Coagulation in Alzheimer’s disease

A Human-Based Integrated Framework forAlzheimer’s Disease Research

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