Glucagon-like peptide-1 mediates effects of oral galactose in streptozotocin-induced rat model of sporadic Alzheimer’s disease

Knezović, Ana; Barilar, Jelena Osmanović; Babić, Ana; Bagarić, Robert; Farkaš, Vladimı́r; Riederer, Peter; Šalković‐Petrišić, Melita

doi:10.1016/j.neuropharm.2018.02.027

Cited by 40 publications

(104 citation statements)

References 106 publications

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“…mediation by glucagon-like peptide 1 (GLP-1) and its neuroprotective, neurotrophic, and neuroendocrine role; as demonstrated in our previous research by galactose-induced increments in plasma levels of active GLP-1 and increased expression of GLP-1 receptor in the hippocampus (GLP-1R) (Knezovic et al, 2018).…”

Section: Introductionmentioning

confidence: 79%

“…Our previous work has shown that chronic oral administration of galactose (a C-epimer of Dglucose) may have therapeutic potential in the STZ-icv rat model of sAD (Knezovic et al, 2018;Salkovic-Petrisic et al, 2014). One-month treatment with 200 mg/kg/day of oral galactose successfully prevented STZ-induced learning and memory deficit when initiated immediately after STZ-icv administration (Salkovic-Petrisic et al, 2014) and 2-month treatment with 200 mg/kg/day of oral galactose normalized already developed impaired learning and memory functions when initiated 1 month after STZ-icv administration (Knezovic et al, 2018). Once absorbed, galactose may be converted into energy by entering the glycolytic pathway after its conversion to glucose-6-phosphate through the Leloir pathway (Frey, 1996;Petry and Reichardt, 1998) and thus restore STZ-induced reduction in brain energy metabolism.…”

Section: Introductionmentioning

confidence: 99%

“…Building on previous results (Knezovic et al, 2018;Salkovic-Petrisic et al, 2014), this research aims to investigate whether oral galactose treatment elicits the same beneficial effect on cognitive deficits in an experimental model of fAD, represented by Tg2576 transgenic mice at 5 and 10 months of age at the initiation of therapy as well as in a mild-to-moderate sAD model using 7 month old rats (4 months after the STZ-icv treatment) at the time of initiation of 2 month oral galactose treatment. Additionally, we aimed to explore the metabolic homeostasis related to GLP-1 in this transgenic model and compare it with the one in the STZ-icv rat model of mild-to-moderate sAD.…”

Section: Introductionmentioning

confidence: 99%

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Cognitive, behavioral and metabolic effects of oral galactose treatment in the transgenic Tg2576 mice

et al. 2019

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Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with insulin resistance and glucose hypometabolism in the brain. Oral administration of galactose, a nutrient that provides an alternative source of energy, prevents and ameliorates early cognitive impairment in a streptozotocin-induced model (STZ-icv) of the sporadic AD (sAD). Here we explored the influence of 2-month oral galactose treatment (200 mg/kg/day) in the familial AD (fAD) by using 5-(5M) and 10-(10M) month-old transgenic Tg2576 mice mimicking the presymptomatic and the mild stage of fAD, and compared it to that observed in 7-month old STZ-icv rats mimicking mild-to-moderate sAD. Cognitive and behavioral performance was tested by Morris Water Maze, Open Field and Elevated Plus Maze tests, and metabolic status by intraperitoneal glucose tolerance test and fluorodeoxyglucose Positron-Emission Tomography scan. The level of insulin, glucagon-like peptide-1 (GLP-1) and soluble amyloid ß1-42 (sAß1-42) was measured by ELISA and the protein expression of insulin receptor (IR), glycogen synthase kinase-3β (GSK-3β), and pre-/post-synaptic markers by Western blot analysis. Although galactose normalized alterations in cerebral glucose metabolism in all Tg2576 mice (5M+2M; 10M+2M) and STZ-icv rats, it did not improve cognitive impairment in either model. Improvement of reduced grooming behavior and normalization in reduced plasma insulin levels were seen only in 5M+2M Tg2576 mice while in 10M+2M Tg2576 mice oral galactose induced metabolic exacerbation at the level of plasma insulin, GLP-1 homeostasis and glucose intolerance, and additionally increased hippocampal sAß1-42 level, decreased IR expression and increased GSK-3β activity. The results indicate that therapeutic potential of oral galactose seems to depend on the stage and the type/model of AD and to differ in the absence and the presence of AD-like pathology.

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Section: Introductionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cognitive, behavioral and metabolic effects of oral galactose treatment in the transgenic Tg2576 mice

et al. 2019

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“…All plasma and CSF samples collected during the study were frozen immediately and stored at −80 • C until further analysis of GLP-1 concentration using a total GLP-1 ELISA kit (Merck Millipore, Billerica, MA, United States) (Knezovic et al, 2018).…”

Section: Determination Of Glp-1 Concentrations and Pka Activitymentioning

confidence: 99%

Brain Endothelial Cells Regulate Glucagon-Like Peptide 1 Entry Into the Brain via a Receptor-Mediated Process

Gong

Liu

et al. 2020

Front. Physiol.

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Glucagon-like peptide 1 (GLP-1) in addition to regulating glucose-dependent insulin and glucagon secretion exerts anorexic and neuroprotective effects. While brain-derived GLP-1 may participate in these central actions, evidence suggests that peripherally derived GLP-1 plays an important role and GLP-1 analogs are known to cross the blood brain barrier. To define the role of brain microvascular endothelial cells in GLP-1 entry into the brain, we infused labeled GLP-1 or exendin-4 into rats intravenously and examined their appearance and protein kinase A activities in various brain regions. We also studied the role of endothelial cell GLP-1 receptor and its signaling in endothelial cell uptake and transport of GLP-1. Systemically infused labeled GLP-1 or exendin-4 appeared rapidly in various brain regions and this was associated with increased protein kinase A activity in these brain regions. Pretreatment with GLP-1 receptor antagonist reduced labeled GLP-1 or exendin-4 enrichment in the brain. Sub-diaphragmatic vagus nerve resection did not alter GLP-1-mediated increases in protein kinase A activity in the brain. Rat brain microvascular endothelial cells rapidly took up labeled GLP-1 and this was blunted by either GLP-1 receptor antagonism or protein kinase A inhibition but enhanced through adenylyl cyclase activation. Using an artificially assembled blood brain barrier consisting of endothelial and astrocyte layers, we found that labeled GLP-1 time-dependently crossed the barrier and the presence of GLP-1 receptor antagonist blunted this transit. We conclude that GLP-1 crosses the blood brain barrier through active trans-endothelial transport which requires GLP-1 receptor binding and activation.

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“…In the course of time, changes in neuronal glucose uptake showed persistent decrease after 1 and 4 weeks Dos Santos et al 2018). FDG-PET studies in rats detected glucose hypometabolism starting from 3 weeks following STZ-icv treatment onward (Chen et al 2018a, b;Knezovic et al 2018;Babic Perhoc et al 2019), which was observed also in STZ-icv treated monkeys after 6 and 12 weeks . Regarding the alterations of GLUTs, consistent findings on decreased levels of GLUT1 and GLUT3 were detected in the brain of the STZ-icv rat model starting from 1 week following treatment (Table 1) Biswas et al 2018).…”

Section: Time Course Of the Appearance Of Insulin Signalling Dysfunctmentioning

confidence: 99%

Shared cerebral metabolic pathology in non-transgenic animal models of Alzheimer's and Parkinson's disease

et al. 2020

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Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common chronic neurodegenerative disorders, characterized by motoric dysfunction or cognitive decline in the early stage, respectively, but often by both symptoms in the advanced stage. Among underlying molecular pathologies that PD and AD patients have in common, more attention is recently paid to the central metabolic dysfunction presented as insulin resistant brain state (IRBS) and altered cerebral glucose metabolism, both also explored in animal models of these diseases. This review aims to compare IRBS and alterations in cerebral glucose metabolism in representative non-transgenic animal PD and AD models. The comparison is based on the selectivity of the neurotoxins which cause experimental PD and AD, towards the cellular membrane and intracellular molecular targets as well as towards the selective neurons/non-neuronal cells, and the particular brain regions. Mitochondrial damage and coexpression of insulin receptors, glucose transporter-2 and dopamine transporter on the membrane of particular neurons as well as astrocytes seem to be the key points which are further discussed in a context of alterations in insulin signalling in the brain and its interaction with dopaminergic transmission, particularly regarding the time frame of the experimental AD/ PD pathology appearance and the correlation with cognitive and motor symptoms. Such a perspective provides evidence on IRBS being a common underlying metabolic pathology and a contributor to neurodegenerative processes in representative non-transgenic animal PD and AD models, instead of being a direct cause of a particular neurodegenerative disorder.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Glucagon-like peptide-1 mediates effects of oral galactose in streptozotocin-induced rat model of sporadic Alzheimer’s disease

Cited by 40 publications

References 106 publications

Cognitive, behavioral and metabolic effects of oral galactose treatment in the transgenic Tg2576 mice

Cognitive, behavioral and metabolic effects of oral galactose treatment in the transgenic Tg2576 mice

Brain Endothelial Cells Regulate Glucagon-Like Peptide 1 Entry Into the Brain via a Receptor-Mediated Process

Shared cerebral metabolic pathology in non-transgenic animal models of Alzheimer's and Parkinson's disease

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