Liraglutide Improves Water Maze Learning and Memory Performance While Reduces Hyperphosphorylation of Tau and Neurofilaments in APP/PS1/Tau Triple Transgenic Mice

Chen, Shuyi; Sun, Jie; Zhao, Gang; Guo, Aihuan; Chen, Yanlin; Fu, Rongxia; Deng, Yanqiu

doi:10.1007/s11064-017-2250-8

Cited by 71 publications

(47 citation statements)

References 39 publications

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“…Data are presented as mean ± SEM. *P < 0.05; **P < 0.01. n = 6/group Cognitive deficits are the main manifestation of AD [34]. In the present study, the data showed that 27-OHC effectively aggravated cognitive deficits in the APP/PS1 mice as shown by the Morris water maze test and the passive avoidance test.…”

Section: Discussionsupporting

confidence: 58%

27-Hydroxycholesterol contributes to cognitive deficits in APP/PS1 transgenic mice through microbiota dysbiosis and intestinal barrier dysfunction

Wang

et al. 2020

J Neuroinflammation

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Background: Research on the brain-gut-microbiota axis has led to accumulating interest in gut microbiota dysbiosis and intestinal barrier dysfunction in Alzheimer's disease (AD). Our previous studies have demonstrated neurotoxic effects of 27-hydroxycholesterol (27-OHC) in in vitro and in vivo models. Here, alterations in the gut microbiota and intestinal barrier functions were investigated as the possible causes of cognitive deficits induced by 27-OHC treatment. Methods: Male APP/PS1 transgenic and C57BL/6J mice were treated for 3 weeks with 27-OHC (5.5 mg/kg/day, subcutaneous injection) and either a 27-OHC synthetase inhibitor (anastrozole, ANS) or saline. The Morris water maze and passive avoidance test were used to assess cognitive impairment. Injuries of the intestine were evaluated by histopathological examination. Intestinal barrier function was assessed by plasma diamine oxidase (DAO) activity and D-lactate. Systemic and intestinal inflammation were evaluated by IL-1β, TNF-α, IL-10, and IL-17 concentrations as determined by ELISA. The fecal microbiome and short-chain fatty acids (SCFAs) were analyzed using 16S rDNA sequencing and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Tight junction proteins were evaluated in the ileum and colon by qRT-PCR and Western blots. Tight junction ultrastructure was examined by transmission electron microscopy. Results: Treatment with 27-OHC resulted in severe pathologies in the ileum and colon. There was impaired intestinal barrier integrity as indicated by dilated tight junctions and downregulation of tight junction proteins, including occludin, claudin 1, claudin 5, and ZO-1, and signs of inflammation (increased IL-1β, TNF-α, and IL-17). Fecal 16S rDNA sequencing and taxonomic analysis further revealed a decreased abundance of Roseburia and reduced fecal levels of several SCFAs in 27-OHC-treated mice. Meanwhile, co-treatment with ANS reduced intestinal inflammation and partially preserved intestinal barrier integrity in the presence of 27-OHC.

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Section: Discussionsupporting

confidence: 58%

27-Hydroxycholesterol contributes to cognitive deficits in APP/PS1 transgenic mice through microbiota dysbiosis and intestinal barrier dysfunction

Wang

et al. 2020

J Neuroinflammation

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“…No other changes in neurocognition were observed in our study. Liraglutide improves spatial memory in rodent models of Alzheimer's disease, but we may not have observed similar changes because of our healthy study population.…”

Section: Discussionmentioning

confidence: 85%

Longer‐term liraglutide administration at the highest dose approved for obesity increases reward‐related orbitofrontal cortex activation in response to food cues: Implications for plateauing weight loss in response to anti‐obesity therapies

Farr

Upadhyay

Rutagengwa

et al. 2019

Diabetes Obesity Metabolism

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Aims GLP‐1 analogs have recently risen to the forefront as effective medications for lowering weight through actions in the central nervous system (CNS). However, their actions in the CNS have not yet been studied in the human brain after longer‐term administration at the highest dose approved for obesity (liraglutide 3.0 mg). Materials and Methods A total of 20 participants with obesity were treated with placebo and liraglutide (3.0 mg) in the context of a randomized, placebo‐controlled, double‐blind, cross‐over trial after 5 weeks of dose escalation. Neurocognitive and neuroimaging (fMRI) responses to food cues were examined at the clinical research center of Beth Israel Deaconess Medical Center. Results While using liraglutide, patients lost more weight (placebo‐subtracted −2.7%; P < .001), had decreased fasting glucose (P < .001) and showed improved cholesterol levels. In an uncontrolled analysis, brain activation in response to food images was not altered by liraglutide vs placebo. When controlled for BMI/weight, liraglutide increased activation of the right orbitofrontal cortex (OFC) in response to food cues (P < .016, corrected for multiple comparisons). Conclusions In contrast to prior studies, we demonstrate for the first time that liraglutide treatment, administered over a longer period at the highest doses approved for obesity, does not alter brain activation in response to food cues. A counter‐regulatory increase in reward‐related OFC activation in response to food cues can be observed when neuroimaging data are controlled for BMI changes, indicating changes in CNS that could lead to later plateaus of weight loss. These data point to a promising focus for additional interventions which, by contributing to the CNS reward system, could provide tangible benefits in reversing the plateauing phenomenon and promoting further weight loss.

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“…Recent evidence suggests hyperphosphorylation of neurofilaments (Chen et al, 2017 ) and decreased MAP-2 levels (Soares et al, 2016 ) in the hippocampus are correlated with cognitive and anxiety dysfunctions in murine models of neurodegeneration and global cerebral ischemia, respectively. In the present study, PA-induced hippocampal accumulation of pNF-H/M and reduction of MAP-2 at P30 exhibited a similar behavioral correlate.…”

Section: Discussionmentioning

confidence: 99%

Palmitoylethanolamide Ameliorates Hippocampal Damage and Behavioral Dysfunction After Perinatal Asphyxia in the Immature Rat Brain

et al. 2018

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Perinatal asphyxia (PA) is an obstetric complication associated with an impaired gas exchange. This health problem continues to be a determinant of neonatal mortality and neurodevelopmental disorders. Palmitoylethanolamide (PEA) has exerted neuroprotection in several models of brain injury and neurodegeneration. We aimed at evaluating the potential neuroprotective role of PEA in an experimental model, which induces PA in the immature rat brain. PA was induced by placing Sprague Dawley newborn rats in a water bath at 37°C for 19 min. Once their physiological conditions improved, they were given to surrogate mothers that had delivered normally within the last 24 h. The control group was represented by non-fostered vaginally delivered pups, mimicking the clinical situation. Treatment with PEA (10 mg/kg) was administered within the first hour of life. Modifications in the hippocampus were analyzed with conventional electron microscopy, immunohistochemistry (for NeuN, pNF-H/M, MAP-2, and GFAP) and western blot (for pNF H/M, MAP-2, and GFAP). Behavior was also studied throughout Open Field (OF) Test, Passive Avoidance (PA) Task and Elevated Plus Maze (EPM) Test. After 1 month of the PA insult, we observed neuronal nucleus degeneration in CA1 using electron microscopy. Immunohistochemistry revealed a significant increase in pNF-H/M and decrease in MAP-2 in CA1 reactive area. These changes were also observed when analyzing the level of expression of these markers by western blot. Vertical exploration impairments and anxiety-related behaviors were encountered in the OF and EPM tests. PEA treatment attenuated PA-induced hippocampal damage and its corresponding behavioral alterations. These results contribute to the elucidation of PEA neuroprotective role after PA and the future establishment of therapeutic strategies for the developing brain.

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Liraglutide Improves Water Maze Learning and Memory Performance While Reduces Hyperphosphorylation of Tau and Neurofilaments in APP/PS1/Tau Triple Transgenic Mice

Cited by 71 publications

References 39 publications

27-Hydroxycholesterol contributes to cognitive deficits in APP/PS1 transgenic mice through microbiota dysbiosis and intestinal barrier dysfunction

27-Hydroxycholesterol contributes to cognitive deficits in APP/PS1 transgenic mice through microbiota dysbiosis and intestinal barrier dysfunction

Longer‐term liraglutide administration at the highest dose approved for obesity increases reward‐related orbitofrontal cortex activation in response to food cues: Implications for plateauing weight loss in response to anti‐obesity therapies

Palmitoylethanolamide Ameliorates Hippocampal Damage and Behavioral Dysfunction After Perinatal Asphyxia in the Immature Rat Brain

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