Blocking IGF Signaling in Adult Neurons Alleviates Alzheimer's Disease Pathology through Amyloid-β Clearance

Gontier, Géraldine; George, Caroline; Chaker, Zayna; Holzenberger, Martin; Aïd, Saba

doi:10.1523/jneurosci.0343-15.2015

Cited by 134 publications

(115 citation statements)

References 64 publications

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“…Furthermore, regulation of prion diseases pathway by miR-27a, miR-146a, and miR-155, reinforces the hypothesis that AMD can be a protein misfolding disease, such as AD, due to deposition of Aβ oligomers in drusen bodies. The potential link between AMD and AD is also in line with the deregulation of insulin receptor signaling by miR-27a, miR-146a, and miR-155 (Giuffrida et al, 2012; Gontier et al, 2015; Takach et al, 2015; Han et al, 2016; Sajan et al, 2016; Table 4A). The set of miRNAs differentially expressed in AMD patients can regulate the same pathways of miRNAs dysregulated in the animal model of AMD (Figure 4 and Table 4B).…”

Section: Resultsmentioning

confidence: 75%

Retinal and Circulating miRNAs in Age-Related Macular Degeneration: An In vivo Animal and Human Study

et al. 2017

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Age related macular degeneration (AMD) is the leading cause of blindness among people aged 50 and over. Retinal deposition of amyloid-β (Aβ) aggregates in AMD patients has suggested a potential link between AMD and Alzheimer's disease (AD). We have evaluated the differential retinal expression profile of miRNAs in a rat model of AMD elicited by Aβ. A serum profile of miRNAs in AMD patients has been also assessed using single TaqMan assay. Analysis of retina from rats intravitreally injected with Aβ revealed that miR-27a, miR-146a, and miR-155 were up-regulated in comparison to control rats. Seven miRNA (miR-9, miR-23a, miR-27a, miR-34a, miR-126, miR-146a, and miR-155) have been found to be dysregulated in serum of AMD patients in comparison to control group. Analysis of pathways has revealed that dysregulated miRNAs, both in the AMD animal model and in AMD patients, can target genes regulating pathways linked to neurodegeneration and inflammation, reinforcing the hypothesis that AMD is a protein misfolding disease similar to AD. In fact, miR-9, miR-23a, miR-27a, miR-34a, miR-146a, miR-155 have been found to be dysregulated both in AMD and AD. In conclusion, we suggest that miR-9, miR-23a, miR-27a, miR-34a, miR-146a, miR-155 represent potential biomarkers and new pharmacological targets for AMD.

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Section: Resultsmentioning

confidence: 75%

Retinal and Circulating miRNAs in Age-Related Macular Degeneration: An In vivo Animal and Human Study

et al. 2017

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“…This is particularly meaningful when considering the mechanisms of aging, since CR, lowering of IGF-1R signaling, and reduction of T b all promote longevity and retard aging independently (25,(38)(39)(40)(41)(42). Temperature reduction prolongs life span in ectothermic as well as endothermic animals (38,40,43,44).…”

Section: Discussionmentioning

confidence: 99%

“…Since constitutive full inactivation of IGF-1R signaling is lethal at birth, genetic deletion was induced in adult mice using Ubc-CreER T2 transgene and homozygous IGF-1R flox knock-in (UBIKOR) (25)(26)(27). Circadian T b profiles of AL-fed UBIKOR and control mice were similar for both sexes (SI Appendix, Fig.…”

Section: Genetic Deletion Of Igf-1r Enhanced the Hypothermic Responsementioning

confidence: 99%

Insulin-like growth factor 1 receptor regulates hypothermia during calorie restriction

Cintrón-Colón

Sanchez‐Alavez

Nguyen

et al. 2017

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

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When food resources are scarce, endothermic animals can lower core body temperature (T b ). This phenomenon is believed to be part of an adaptive mechanism that may have evolved to conserve energy until more food becomes available. Here, we found in the mouse that the insulin-like growth factor 1 receptor (IGF-1R) controls this response in the central nervous system. Pharmacological or genetic inhibition of IGF-1R enhanced the reduction of temperature and of energy expenditure during calorie restriction. Full blockade of IGF-1R affected female and male mice similarly. In contrast, genetic IGF-1R dosage was effective only in females, where it also induced transient and estrusspecific hypothermia in animals fed ad libitum. These effects were regulated in the brain, as only central, not peripheral, pharmacological activation of IGF-1R prevented hypothermia during calorie restriction. Targeted IGF-1R knockout selectively in forebrain neurons revealed that IGF signaling also modulates calorie restriction-dependent T b regulation in regions rostral of the canonical hypothalamic nuclei involved in controlling body temperature. In aggregate, these data identify central IGF-1R as a mediator of the integration of nutrient and temperature homeostasis. They also show that calorie restriction, IGF-1R signaling, and body temperature, three of the main regulators of metabolism, aging, and longevity, are components of the same pathway.IGF-1R | temperature | calorie restriction | energy homeostasis | aging

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“…IIS can suppress Aβ production [163] and resulting tissue damage [164] although its full role in AD is still unclear [165, 166]. Deeper understanding is necessary as it may become an attractive target in the future treatment of AD and PD [167].…”

Section: Sirtuins In Neurodegeneration and Neuroprotectionmentioning

confidence: 99%

Sirtuins and Their Roles in Brain Aging and Neurodegenerative Disorders

et al. 2016

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Sirtuins (SIRT1–SIRT7) are unique histone deacetylases (HDACs) whose activity depends on NAD+ levels and thus on the cellular metabolic status. SIRTs regulate energy metabolism and mitochondrial function. They orchestrate the stress response and damage repair. Through these functions sirtuins modulate the course of aging and affect neurodegenerative diseases. SIRTSs interact with multiple signaling proteins, transcription factors (TFs) and poly(ADP-ribose) polymerases (PARPs) another class of NAD+-dependent post-translational protein modifiers. The cross-talk between SIRTs TFs and PARPs is a highly promising research target in a number of brain pathologies. This review describes updated results on sirtuins in brain aging/neurodegeneration. It focuses on SIRT1 but also on the roles of mitochondrial SIRTs (SIRT3, 4, 5) and on SIRT6 and SIRT2 localized in the nucleus and in cytosol, respectively. The involvement of SIRTs in regulation of insulin-like growth factor signaling in the brain during aging and in Alzheimer’s disease was also focused. Moreover, we analyze the mechanism(s) and potential significance of interactions between SIRTs and several TFs in the regulation of cell survival and death. A critical view is given on the application of SIRT activators/modulators in therapy of neurodegenerative diseases.

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Blocking IGF Signaling in Adult Neurons Alleviates Alzheimer's Disease Pathology through Amyloid-β Clearance

Cited by 134 publications

References 64 publications

Retinal and Circulating miRNAs in Age-Related Macular Degeneration: An In vivo Animal and Human Study

Retinal and Circulating miRNAs in Age-Related Macular Degeneration: An In vivo Animal and Human Study

Insulin-like growth factor 1 receptor regulates hypothermia during calorie restriction

Sirtuins and Their Roles in Brain Aging and Neurodegenerative Disorders

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