Exenatide exerts cognitive effects by modulating the BDNF-TrkB neurotrophic axis in adult mice

Bomba, Manuela; Granzotto, Alberto; Castelli, Vanessa; Massetti, Noemi; Silvestri, Elena; Canzoniero, Lorella M.T.; Cimini, Annamaria; Sensi, Stefano L.

doi:10.1016/j.neurobiolaging.2017.12.009

Cited by 57 publications

(50 citation statements)

References 104 publications

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“…Although ERK1,2 activation has been previously considered as a critical step for the BDNF signaling cascade, a growing body of recent evidence has challenged the positive effect of pERK1,2 and shown that the molecules participate in several death-related mechanisms (reviewed in 53 ). In that regard and in line with our previous findings 26 , our results support the idea that ERK1,2 promotes divergent and bimodal effects and indicate a deleterious HFD-driven activation of ERK1,2 54 .…”

Section: Molecular Effects Of Hfd On 3xtg-ad Micesupporting

confidence: 92%

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Exenatide reverts the high-fat-diet-induced impairment of BDNF signaling and inflammatory response in an animal model of Alzheimer’s disease

Bomba

Granzotto

Castelli

et al. 2018

Preprint

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Background: preclinical, clinical, and epidemiological evidence support the notion that Alzheimer's disease (AD) is a multifactorial condition in which, along with β-amyloid (Aβ) and tau-related pathology, the synergistic activity of genetic, environmental, vascular, metabolic, and inflammatory factors promote the onset and progression of the disease. Epidemiological evidence indicate that glucose intolerance, deficits in insulin secretion or type 2 diabetes mellitus (T2DM) participate in increasing the risk of developing cognitive impairment or dementia. A pivotal role in the process is played by insulin as the hormone critically regulates brain functioning. GLP-1, the glucagon-like peptide 1, facilitates insulin signaling, regulates glucose homeostasis, and modulates synaptic plasticity. Exenatide is a GLP-1R agonist, characterized by an extended half-life, employed in T2DM. However, exenatide has also been shown to affect the signaling of the brain-derived neurotrophic factor (BDNF), synaptic plasticity, and cognitive performances in animal models of brain aging and neurodegeneration.Methods: in this study, we tested whether exenatide exerts neuroprotection in a preclinical AD model set to mimic the clinical complexity of the human disease. To that aim, we investigated the effects of 3-month exenatide treatment in 3xTg-AD mice challenged for six months with a high-fat diet (HFD). Endpoints of the study were variations in systemic metabolism, insulin and neurotrophic signaling, neuroinflammation, levels of Aβ and tau pathology as well as changes in cognitive performances. Findings and interpretation:results of the study indicate that exenatide reverts the adverse changes of BDNF signaling and the neuroinflammation status of 3xTg-AD mice undergoing HFD.

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Section: Molecular Effects Of Hfd On 3xtg-ad Micesupporting

confidence: 92%

“…CD consists of a standard chow with 13% of energy deriving from fats. Exenatide or vehicle administration were performed as previously described 26 . Briefly, exenatide (500 μg/kg body weight) or vehicle were administered via intraperitoneal injection five days per…”

Section: Animals and Treatment Paradigmmentioning

confidence: 99%

Exenatide reverts the high-fat-diet-induced impairment of BDNF signaling and inflammatory response in an animal model of Alzheimer’s disease

Bomba

Granzotto

Castelli

et al. 2018

Preprint

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“…We found that aged neurons exhibit higher expression levels of p53 and increased activation of pJNK and pP38, three molecules implicated in neuronal demise 48,49 . In parallel, we observed an age-dependent decrease in the levels of the prosurvival kinases pAKT and pERK5 32,50 .…”

Section: Age-related Functional and Molecular Changes On Cultured Cormentioning

confidence: 57%

“…Western blot analysis was performed as previously described 78,79 . Briefly, control and treated cells were lysed in ice-cold RIPA buffer (phosphate buffer saline pH 7.4 containing 0.5% sodium deoxycholate, 1% Igepal, 0.1% SDS, 5mM EDTA, 1% protease and phosphatase inhibitor cocktails).…”

Section: Western Blot Analysismentioning

confidence: 99%

Inhibition ofde novoceramide biosynthesis affects aging phenotype in anin vitromodel of neuronal senescence

Granzotto

Bomba

Castelli

et al. 2019

Preprint

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Although aging is considered to be an unavoidable event, recent experimental evidence suggests that the process can be delayed, counteracted, if not completely interrupted. Aging is the primary risk factor for the onset and development of neurodegenerative conditions like Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Intracellular calcium (Ca 2+ i) dyshomeostasis, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are critical factors that contribute to senescence-related processes. Ceramides, a class of sphingolipids involved in a wide array of biological functions, are important mediators of cellular senescence, but their role in neuronal aging is still largely unexplored.In this study, we investigated the effects of L-cycloserine (L-CS), an inhibitor of de novo ceramide biosynthesis, on the aging phenotype of cortical neurons that have been maintained in culture for 22 days, a setting employed as an in vitro model of cellular senescence. Our findings indicate that 'aged' neurons display, when compared to control cultures, overt dysregulation of cytosolic and subcellular [Ca 2+ ]i levels, mitochondrial dysfunction, increased reactive oxygen species generation, altered synaptic activity as well as the activation of neuronal death-related molecules. Treatment with L-CS (30 µM) positively affected the senescent phenotype, a result accompanied by recovery of neuronal [Ca 2+ ]i signaling, and reduction of mitochondrial dysfunction and reactive oxygen species generation.The results suggest that the de novo ceramide biosynthesis may represent a critical intermediate in the molecular and functional cascade leading to neuronal senescence. Our findings also identify ceramide biosynthesis inhibitors as promising pharmacological tools to decrease agerelated neuronal dysfunctions. L-CS treatment does not modify NCX activityCeramides can modulate the activity of the plasmalemmal Na + -Ca 2+ exchanger (NCX) 25 , a low capacitance high-affinity system that critically regulates cellular [Ca 2+ ]i. We, therefore, investigated

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“…They have been shown to have anti‐inflammatory effects in some laboratories, however, these properties may not be necessarily relevant to their therapeutic effects . There are data indicating beneficial effects on mitochondrial function, as well as through enhancing the actions of the neurotrophic factor BDNF . It is likely that all of these actions are inter‐related, possibly through an effect of GLP‐1 receptor stimulation on insulin resistance and downstream Akt signaling …”

Section: Glp‐1 Effects In Laboratory Models Of Pdmentioning

confidence: 99%

Glucagon‐like Peptides (GLP‐1) Perspectives in Synucleinopathies Treatment

Foltynie

2018

Movement Disord Clin Pract

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Exenatide exerts cognitive effects by modulating the BDNF-TrkB neurotrophic axis in adult mice

Cited by 57 publications

References 104 publications

Exenatide reverts the high-fat-diet-induced impairment of BDNF signaling and inflammatory response in an animal model of Alzheimer’s disease

Exenatide reverts the high-fat-diet-induced impairment of BDNF signaling and inflammatory response in an animal model of Alzheimer’s disease

Inhibition ofde novoceramide biosynthesis affects aging phenotype in anin vitromodel of neuronal senescence

Glucagon‐like Peptides (GLP‐1) Perspectives in Synucleinopathies Treatment

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