Insulin and Autophagy in Neurodegeneration

Mello, Natalia Prudente de; Orellana, Ana Maria; Mazucanti, Caio Henrique; Lima, Gerusa Marcondes Pimentel de Abreu; Scavone, Cristóforo; Kawamoto, Elisa Mitiko

doi:10.3389/fnins.2019.00491

Cited by 43 publications

(38 citation statements)

References 177 publications

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“…This primordial membrane is called phagophore, which will, in a second step, fuse at its edges forming a double-membrane vesicle called autophagosome. The autophagosomes will undergo a maturation step in which they fuse with acidified lysosomal or endosomal vesicles to finally degrade a damaged element and recycle it ( Figure 3A) (160,161).…”

Section: Autophagy In Aged Brainmentioning

confidence: 99%

Effects of Physical Exercise on Autophagy and Apoptosis in Aged Brain: Human and Animal Studies

et al. 2020

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The aging process is characterized by a series of molecular and cellular changes over the years that could culminate in the deterioration of physiological parameters important to keeping an organism alive and healthy. Physical exercise, defined as planned, structured and repetitive physical activity, has been an important force to alter physiology and brain development during the process of human beings' evolution. Among several aspects of aging, the aim of this review is to discuss the balance between two vital cellular processes such as autophagy and apoptosis, based on the fact that physical exercise as a non-pharmacological strategy seems to rescue the imbalance between autophagy and apoptosis during aging. Therefore, the effects of different types or modalities of physical exercise in humans and animals, and the benefits of each of them on aging, will be discussed as a possible preventive strategy against neuronal death.

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Section: Autophagy In Aged Brainmentioning

confidence: 99%

Effects of Physical Exercise on Autophagy and Apoptosis in Aged Brain: Human and Animal Studies

et al. 2020

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“…Further, we performed the knowledge-based ingenuity pathway analysis (IPA) tool to identify the common pathways which could be dysregulated in the brain. We found that sirtuin signalling pathway 63 , cardiac hypertrophy signalling, estrogen receptor signalling, insulin secretion signalling 64 and signalling by Rho Family GTPases were upregulated in DJ-1 −/− mice while hepatic fibrosis signaling pathway, endothelin-1 signalling, ephrin receptor signalling, fMLP signalling in neutrophils were down regulated based on Z-score ( Fig. 6c).…”

Section: Increased Inflammatory Genes Related To Pd In Dj-1 −/− Mice mentioning

confidence: 86%

DJ-1 (Park7) affects the gut microbiome, metabolites and the development of innate lymphoid cells (ILCs)

Singh

Trautwein

Dhariwal

et al. 2020

Sci Rep

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The proper communication between gut and brain is pivotal for the maintenance of health and, dysregulation of the gut-brain axis can lead to several clinical disorders. In Parkinson’s disease (PD) 85% of all patients experienced constipation many years before showing any signs of motor phenotypes. For differential diagnosis and preventive treatment, there is an urgent need for the identification of biomarkers indicating early disease stages long before the disease phenotype manifests. DJ-1 is a chaperone protein involved in the protection against PD and genetic mutations in this protein have been shown to cause familial PD. However, how the deficiency of DJ-1 influences the risk of PD remains incompletely understood. In the present study, we provide evidence that DJ-1 is implicated in shaping the gut microbiome including; their metabolite production, inflammation and innate immune cells (ILCs) development. We revealed that deficiency of DJ-1 leads to a significant increase in two specific genera/species, namely Alistipes and Rikenella. In DJ-1 knock-out (DJ-1-/-) mice the production of fecal calprotectin and MCP-1 inflammatory proteins were elevated. Fecal and serum metabolic profile showed that malonate which influences the immune system was significantly more abundant in DJ-1−/− mice. DJ-1 appeared also to be involved in ILCs development. Further, inflammatory genes related to PD were augmented in the midbrain of DJ-1−/− mice. Our data suggest that metabolites and inflammation produced in the gut could be used as biomarkers for PD detection. Perhaps, these metabolites and inflammatory mediators could be involved in triggering inflammation resulting in PD pathology.

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“…This in turn was associated with an increased mTORC phosphorylation at the Akt sensitive site, Ser2448 (43). Multiple lines of evidence implicate the activation of the insulin receptor/Akt/mTORC signaling pathway in suppression of autophagy associated with insulin resistance in neurons (67) and peripheral tissue (68). mTORC activation represses the activity of the unc-51-like kinase 1 (ULK1) via phosphorylation, and thus precludes autophagosome maturation (69).…”

Section: Discussionmentioning

confidence: 99%

Dysfunctional cerebrovascular tone contributes to cognitive impairment in a non-obese rat model of prediabetic challenge: Role of suppression of autophagy and modulation by anti-diabetic drugs

Fakih

Mroueh

Salah

et al. 2019

Preprint

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Early stages of metabolic dysfunction, including prediabetes, pose a high risk for cardiovascular and cognitive impairment. While several pathological mechanisms linked advanced manifestations of metabolic deterioration, such as hypoglycemia, to neuronal inflammation and cognitive decline, little is known about the detrimental processes in effect at the early stages. To address this gap, we used a non-obese rat model of prediabetes developed in our laboratory. After 12 weeks of mild hypercaloric feeding, these rats developed hyperinsulinemia and increased fat/lean ratio without an increase in blood glucose level or body weight. These rats showed vascular dysfunction manifested as exaggerated contractility as a consequence of perivascular adipose inflammation. In this study, the mild metabolic challenge was associated with impaired hippocampal-dependent cognitive functions, spatial learning and memory and spontaneous object recognition. In line with our previous findings in this model, prediabetic rats had an augmented cerebrovascular myogenic tone demonstrated as an increased pressure-evoked contraction in pressure myography experiments on rat middle cerebral artery segments. The presumed brain hypoperfusion was accompanied by increased expression of hypoxia-inducible factor-1a in the hippocampus, together with markers of mitochondrial dysfunction and increased oxidative stress. In parallel, increased p62 expression and LC3 puncta in the prediabetic rat hippocampus, as well as increased Akt and mammalian target of rapamycin phosphorylation indicated a possible repression of autophagic flux. Consequently, the examination of the hippocampal CA1 area revealed increased CD68 and IBA-1 staining consistent with microglial activation and neuroinflammation, in addition to increased TUNEL staining and caspase-3 activity indicative of elevated neuronal apoptosis. Interestingly, a two-week treatment with non-hypoglycemic doses of metformin or pioglitazone, previously shown to improve adipose inflammation and vascular function, reversed the cerebrovascular and molecular alterations in the hippocampus. This was associated with an amelioration of cognitive function. The results of the present study indicate that early metabolic challenge leads to cerebrovascular alteration potentially leading to hippocampal hypoxia and mitochondrial dysfunction. Together with suppression of autophagy, these effects culminate in hippocampal inflammation and apoptosis possibly underlying the cognitive impairment.

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Insulin and Autophagy in Neurodegeneration

Cited by 43 publications

References 177 publications

Effects of Physical Exercise on Autophagy and Apoptosis in Aged Brain: Human and Animal Studies

Effects of Physical Exercise on Autophagy and Apoptosis in Aged Brain: Human and Animal Studies

DJ-1 (Park7) affects the gut microbiome, metabolites and the development of innate lymphoid cells (ILCs)

Dysfunctional cerebrovascular tone contributes to cognitive impairment in a non-obese rat model of prediabetic challenge: Role of suppression of autophagy and modulation by anti-diabetic drugs

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