Can insulin signaling pathways be targeted to transport AÎ² out of the brain?

Vandal, Milène; Bourassa, Philippe

doi:10.3389/fnagi.2015.00114

Cited by 26 publications

(26 citation statements)

References 185 publications

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“…Corresponding to this compensatory mechanism, the present study expectedly demonstrated an increased fasting serum insulin level following IR, which directly implicated that physiological hyperinsulinemia ocurred in response to NO2 inhalation. Insulin in the serum is transported by the CSF and can cross the BBB into the brain (Vandal et al, 2015). There is evidence that chronic peripheral hyperinsulinemia (as occurs in IR) leads to a reduction of insulin transport across the BBB and affects all of the actions of insulin in the brain (Neumann et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

NO2 inhalation causes tauopathy by disturbing the insulin signaling pathway

Yan

Yue

et al. 2016

Chemosphere

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Air pollution has been evidenced as a risk factor for neurodegenerative tauopathies. NO, a primary component of air pollution, is negatively linked to neurodegenerative disorders, but its independent and direct association with tau lesion remains to be elucidated. Considering the fact that the insulin signaling pathway can be targeted by air pollutants and regulate tau function, this study focused on the role of insulin signaling in this NO-induced tauopathy. Using a dynamic inhalation treatment, we demonstrated that exposure to NO induced a disruption of insulin signaling in skeletal muscle, liver, and brain, with associated p38 MAPK and/or JNK activation. We also found that in parallel with these kinase signaling cascades, the compensatory hyperinsulinemia triggered by whole-body insulin resistance (IR) further attenuated the IRS-1/AKT/GSK-3β signaling pathway in the central nervous system, which consequently increased the phosphorylation of tau and reduced the expression of synaptic proteins that contributed to the development of the tau pathology. These findings provide new insight into the possible mechanisms involved in the etiopathogenesis of NO-induced tauopathy, suggesting that the targeting of insulin signaling may be a promising therapeutic strategy to prevent this disease.

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Section: Discussionmentioning

confidence: 99%

NO2 inhalation causes tauopathy by disturbing the insulin signaling pathway

Yan

Yue

et al. 2016

Chemosphere

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“…The characteristic changes in the brain tissue of AD patients are: (a) hyperphosphorylated tau protein rich intra-neuronal neurofibrillary tangles (NFT); (b) extracellular senile plaques of aggregated amyloid β (Aβ) peptides; and (c) brain tissue atrophy, starting in the entorhinal region and the temporal lobe, and progressing to the limbic system and the neocortex [ 4 , 5 , 6 , 7 , 8 , 9 ]. Most patients with AD have a sporadic, late onset form, where the major risk factors are aging, type 2 diabetes (T2D) and apolipoprotein E ε4 (APOE-ε4) [ 10 , 11 , 12 , 13 , 14 , 15 ].…”

Section: Etiology Of Admentioning

confidence: 99%

Peptides as Potential Therapeutics for Alzheimer’s Disease

Ribarič

2018

Molecules

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Intracellular synthesis, folding, trafficking and degradation of proteins are controlled and integrated by proteostasis. The frequency of protein misfolding disorders in the human population, e.g., in Alzheimer’s disease (AD), is increasing due to the aging population. AD treatment options are limited to symptomatic interventions that at best slow-down disease progression. The key biochemical change in AD is the excessive accumulation of per-se non-toxic and soluble amyloid peptides (Aβ(1-37/44), in the intracellular and extracellular space, that alters proteostasis and triggers Aβ modification (e.g., by reactive oxygen species (ROS)) into toxic intermediate, misfolded soluble Aβ peptides, Aβ dimers and Aβ oligomers. The toxic intermediate Aβ products aggregate into progressively less toxic and less soluble protofibrils, fibrils and senile plaques. This review focuses on peptides that inhibit toxic Aβ oligomerization, Aβ aggregation into fibrils, or stabilize Aβ peptides in non-toxic oligomers, and discusses their potential for AD treatment.

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“…Similarly, the regulated transport of soluble Aβ monomers across the blood-brain barrier by low-density lipoprotein receptor-related protein 1, ATP binding cassette transporters, and advanced glycation end product-specific receptor is critical to maintaining non-cytotoxic levels of Aβ in the brain (Shibata et al, 2000; Deane et al, 2003). Importantly, diverse intercellular and metabolic signals such as insulin might have a direct role in the regulation of Aβ transport into and out of neural tissues (Vandal et al, 2015). …”

Section: Neurodegenerative Disorders: Ipsc Models Induced Neuralmentioning

confidence: 99%

The therapeutic potential of cell identity reprogramming for the treatment of aging-related neurodegenerative disorders

Zhang

Zheng

2017

Progress in Neurobiology

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Neural cell identity reprogramming strategies aim to treat age-related neurodegenerative disorders with newly induced neurons that regenerate neural architecture and functional circuits in vivo. The isolation and neural differentiation of pluripotent embryonic stem cells provided the first in vitro models of human neurodegenerative disease. Investigation into the molecular mechanisms underlying stem cell pluripotency revealed that somatic cells could be reprogrammed to induced pluripotent stem cells (iPSCs) and these cells could be used to model Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, and Parkinson disease. Additional neural precursor and direct transdifferentiation strategies further enabled the induction of diverse neural linages and neuron subtypes both in vitro and in vivo. In this review, we highlight neural induction strategies that utilize stem cells, iPSCs, and lineage reprogramming to model or treat age-related neurodegenerative diseases, as well as, the clinical challenges related to neural transplantation and in vivo reprogramming strategies.

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Can insulin signaling pathways be targeted to transport AÎ² out of the brain?

Cited by 26 publications

References 185 publications

NO2 inhalation causes tauopathy by disturbing the insulin signaling pathway

NO2 inhalation causes tauopathy by disturbing the insulin signaling pathway

Peptides as Potential Therapeutics for Alzheimer’s Disease

The therapeutic potential of cell identity reprogramming for the treatment of aging-related neurodegenerative disorders

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