• diseases of the nervous system
• metabolism

• Animals
• Male
• Mice
• Brain/metabolism
• Brain/diagnostic imaging
• Fluorodeoxyglucose F18
• Glucagon-Like Peptide 1/metabolism
• Glucagon-Like Peptide-1 Receptor/metabolism
• Glucose/metabolism
• Magnetic Resonance Imaging
• Mice, Inbred C57BL
• Mice, Knockout
• Positron-Emission Tomography/methods

• 81950410637 National Natural Science Foundation of China (National Science Foundation of China)
• 32100555 National Natural Science Foundation of China (National Science Foundation of China)

• Alzheimer's disease (AD)
• Dementia
• Diabetes
• Glucose metabolism
• Insulin signaling
• Mitochondrial dysfunction
• Neurodegenerative diseases

• Humans
• Alzheimer Disease/metabolism
• Amyloid beta-Peptides/metabolism
• Phosphatidylinositol 3-Kinases/metabolism
• Oxidative Stress/physiology
• Mitochondria/metabolism
• Glucose/metabolism
• Insulin/metabolism
• Disease Progression

• R01 AG042178 NIA NIH HHS
• R01 NS105473 NINDS NIH HHS

The most common cause of dementia, especially in elderly people, is Alzheimer’s disease (AD), with aging as its main risk factor. AD is a multifactorial neurodegenerative disease. There are several factors increasing the risk of AD development. One of the main features of Alzheimer’s disease is impairment of brain energy. Hypometabolism caused by decreased glucose uptake is observed in specific areas of the AD-affected brain. Therefore, glucose hypometabolism and energy deficit are hallmarks of AD. There are several hypotheses that explain the role of glucose hypometabolism in AD, but data available on this subject are poor. Reduced transport of glucose into neurons may be related to decreased expression of glucose transporters in neurons and glia. On the other hand, glucose transporters may play a role as potential targets for the treatment of AD. Compounds such as antidiabetic drugs, agonists of SGLT1, insulin, siRNA and liposomes are suggested as therapeutics. Nevertheless, the suggested targets of therapy need further investigations.

• Alzheimer’s disease
• glucose transporters
• hypometabolism
• therapy of Alzheimer’s disease

• Acute ischemic stroke
• Diabetes mellitus
• Dipeptidyl Peptidase-IV Inhibitors
• Glucagon-like 1 receptor agonists
• Hyperglycemia

• Bipolar disorder
• GLP-1R agonists
• Glucagon-like peptide-1
• Insulin resistance
• Liraglutide
• Major depressive disorder
• Obesity
• Weight loss

• Anxiety
• Depression
• Gut microbiota
• Gut peptides
• Gut–brain axis

• Anxiety/metabolism
• Anxiety/microbiology
• Brain/metabolism
• Brain/microbiology
• Cholecystokinin/metabolism
• Corticotropin-Releasing Hormone/metabolism
• Depression/metabolism
• Depression/microbiology
• Endocrine System/metabolism
• Endocrine System/microbiology
• Gastrointestinal Microbiome
• Ghrelin/metabolism
• Glucagon-Like Peptide 1/metabolism
• Humans
• Neuropeptide Y/metabolism
• Oxytocin/metabolism
• Peptide Hormones/metabolism

• Cerebral glucose metabolism
• GLP-1
• Incretin hormones

There are fewer than normal glucose transporters at the blood-brain barrier (BBB) in Alzheimer’s disease (AD). When reduced expression of transporters aggravates the symptoms of AD, the transporters become a potential target of therapy. The incretin hormone GLP-1 prevents the decline of cerebral metabolic rate for glucose (CMR_glc) in AD, and GLP-1 may serve to raise transporter numbers. We hypothesized that the GLP-1 analog liraglutide would prevent the decline of CMR_glc in AD by raising blood-brain glucose transfer, depending on the duration of disease. We randomized 38 patients with AD to treatment with liraglutide (n = 18) or placebo (n = 20) for 6 months, and determined the blood-brain glucose transfer capacity (T_max) in the two groups and a healthy age matched control group (n = 6). In both AD groups at baseline, T_max estimates correlated inversely with the duration of AD, as did the estimates of CMR_glc that in turn were positively correlated with cognition. The GLP-1 analog treatment, compared to placebo, highly significantly raised the T_max estimates of cerebral cortex from 0.72 to 1.1 umol/g/min, equal to T_max estimates in healthy volunteers. The result is consistent with the claim that GLP-1 analog treatment restores glucose transport at the BBB.

• Alzheimer’s disease
• Bariatric surgery
• Dementia
• Diabetes
• Gastric bypass
• Glucagon-like peptide 1
• Insulin
• Metabolic surgery
• Obesity
• Weight loss

• appetite
• central nervous system
• glucagon-like peptide-1
• neurodegenerative diseases
• type 2 diabetes

• Animals
• Central Nervous System/metabolism
• Diabetes Mellitus/metabolism
• Diabetes Mellitus, Type 2/metabolism
• Glucagon-Like Peptide 1/metabolism
• Humans
• Neurodegenerative Diseases/metabolism
• Peripheral Nervous System/metabolism

• Alzheimer’s disease
• CBF
• [11C] PiB
• amyloid-β
• flow normalization
• parametric imaging

Introduction: Traumatic brain injury is a major cause of mortality and morbidity. We have previously shown that the injectable glucagon-like peptide-1 (GLP-1) analog, liraglutide, significantly improved the outcome in mice after severe traumatic brain injury (TBI). In this study we are interested in the effects of oral treatment of a different class of GLP-1 based therapy, dipeptidyl peptidase IV (DPP-IV) inhibition on mice after TBI. DPP-IV inhibitors reduce the degradation of endogenous GLP-1 and extend circulation of this protective peptide in the bloodstream. This class has yet to be investigated as a potential therapy for TBI.

Methods: Mice were administrated once-daily 50 mg/kg of sitagliptin in a Nutella® ball or Nutella® alone throughout the study, beginning 2 days before severe trauma was induced with a stereotactic cryo-lesion. At 2 days post trauma, lesion size was determined. Brains were isolated for immunoblotting for assessment of selected biomarkers for pathology and protection.

Results: Sitagliptin treatment reduced lesion size at day 2 post-injury by ~28% (p < 0.05). Calpain-driven necrotic tone was reduced ~2-fold in sitagliptin-treated brains (p < 0.001) and activation of the protective cAMP-response element binding protein (CREB) system was significantly more pronounced (~1.5-fold, p < 0.05). The CREB-regulated, mitochondrial antioxidant protein manganese superoxide dismutase (MnSOD) was increased in sitagliptin-treated mice (p < 0.05). Conversely, apoptotic tone (alpha-spectrin fragmentation, Bcl-2 levels) and the neuroinflammatory markers IL-6, and Iba-1 were not affected by treatment.

Conclusions: This study shows, for the first time, that DPP-IV inhibition ameliorates both anatomical and biochemical consequences of TBI and activates CREB in the brain. Moreover, this work supports previous studies suggesting that the effect of GLP-1 analogs in models of brain damage relates to GLP-1 receptor stimulation in a dose-dependent manner.

• CREB
• DPP-IV
• GIP
• GLP-1
• TBI
• liraglutide
• sitagliptin
• traumatic brain injury

• APP
• EAE
• GLP-1
• MS
• MnSOD
• liraglutide
• multiple sclerosis

Recent studies indicate that glucagon-like peptide 1 (GLP-1) receptor agonists, currently used in the management of type 2 diabetes, exhibit neurotrophic and neuroprotective effects in amyloid-β (Aβ) toxicity models of Alzheimer’s disease (AD). We investigated the potential pro-cognitive and neuroprotective effects of the once-daily GLP-1 receptor agonist liraglutide in senescence-accelerated mouse prone 8 (SAMP8) mice, a model of age-related sporadic AD not dominated by amyloid plaques. Six-month-old SAMP8 mice received liraglutide (100 or 500 μg/kg/day, s.c.) or vehicle once daily for 4 months. Vehicle-dosed age-matched 50% back-crossed as well as untreated young (4-month-old) SAMP8 mice were used as control groups for normal memory function. Vehicle-dosed 10-month-old SAMP8 mice showed significant learning and memory retention deficits in an active-avoidance T-maze, as compared to both control groups. Also, 10-month-old SAMP8 mice displayed no immunohistological signatures of amyloid-β plaques or hyperphosphorylated tau, indicating the onset of cognitive deficits prior to deposition of amyloid plaques and neurofibrillary tangles in this AD model. Liraglutide significantly increased memory retention and total hippocampal CA1 pyramidal neuron numbers in SAMP8 mice, as compared to age-matched vehicle-dosed SAMP8 mice. In conclusion, liraglutide delayed or partially halted the progressive decline in memory function associated with hippocampal neuronal loss in a mouse model of pathological aging with characteristics of neurobehavioral and neuropathological impairments observed in early-stage sporadic AD.

• Alzheimer’s disease
• GLP-1 receptor agonist
• SAMP8 mouse
• hippocampus
• liraglutide
• memory function
• neuroprotection
• stereology

In animal models, the incretin hormone GLP-1 affects Alzheimer’s disease (AD). We hypothesized that treatment with GLP-1 or an analog of GLP-1 would prevent accumulation of Aβ and raise, or prevent decline of, glucose metabolism (CMR_glc) in AD. In this 26-week trial, we randomized 38 patients with AD to treatment with the GLP-1 analog liraglutide (n = 18), or placebo (n = 20). We measured Aβ load in brain with tracer [¹¹C]PIB (PIB), CMR_glc with [¹⁸F]FDG (FDG), and cognition with the WMS-IV scale (ClinicalTrials.gov NCT01469351). The PIB binding increased significantly in temporal lobe in placebo and treatment patients (both P = 0.04), and in occipital lobe in treatment patients (P = 0.04). Regional and global increases of PIB retention did not differ between the groups (P ≥ 0.38). In placebo treated patients CMR_glc declined in all regions, significantly so by the following means in precuneus (P = 0.009, 3.2 μmol/hg/min, 95% CI: 5.45; 0.92), and in parietal (P = 0.04, 2.1 μmol/hg/min, 95% CI: 4.21; 0.081), temporal (P = 0.046, 1.54 μmol/hg/min, 95% CI: 3.05; 0.030), and occipital (P = 0.009, 2.10 μmol/hg/min, 95% CI: 3.61; 0.59) lobes, and in cerebellum (P = 0.04, 1.54 μmol/hg/min, 95% CI: 3.01; 0.064). In contrast, the GLP-1 analog treatment caused a numerical but insignificant increase of CMR_glc after 6 months. Cognitive scores did not change. We conclude that the GLP-1 analog treatment prevented the decline of CMR_glc that signifies cognitive impairment, synaptic dysfunction, and disease evolution. We draw no firm conclusions from the Aβ load or cognition measures, for which the study was underpowered.

• Alzheimer’s disease
• amyloid
• cerebral glucose metabolism
• glucagon-like peptide-1
• liraglutide

Long-acting glucagon-like peptide-1 (GLP-1) analogues marketed for type 2 diabetes (T2D) treatment have been showing positive and protective effects in several different tissues, including pancreas, heart or even brain. This gut secreted hormone plays a potent insulinotropic activity and an important role in maintaining glucose homeostasis. Furthermore, growing evidences suggest the occurrence of several commonalities between T2D and neurodegenerative diseases, insulin resistance being pointed as a main cause for cognitive decline and increased risk to develop dementia. In this regard, it has also been suggested that stimulation of brain insulin signaling may have a protective role against cognitive deficits. As GLP-1 receptors (GLP-1R) are expressed throughout the central nervous system and GLP-1 may cross the blood-brain-barrier, an emerging hypothesis suggests that they may be promising therapeutic targets against brain dysfunctional insulin signaling-related pathologies. Importantly, GLP-1 actions depend not only on the direct effect mediated by its receptor activation, but also on the gut-brain axis involving an exchange of signals between both tissues via the vagal nerve, thereby regulating numerous physiological functions (e.g., energy homeostasis, glucose-dependent insulin secretion, as well as appetite and weight control). Amongst the incretin/GLP-1 mimetics class of anti-T2D drugs with an increasingly described neuroprotective potential, the already marketed liraglutide emerged as a GLP-1R agonist highly resistant to dipeptidyl peptidase-4 degradation (thereby having an increased half-life) and whose systemic GLP-1R activity is comparable to that of native GLP-1. Importantly, several preclinical studies showed anti-apoptotic, anti-inflammatory, anti-oxidant and neuroprotective effects of liraglutide against T2D, stroke and Alzheimer disease (AD), whereas several clinical trials, demonstrated some surprising benefits of liraglutide on weight loss, microglia inhibition, behavior and cognition, and in AD biomarkers. Herein, we discuss the GLP-1 action through the gut-brain axis, the hormone’s regulation of some autonomic functions and liraglutide’s neuroprotective potential.

• Type 2 diabetes
• Glucagon-like peptide-1
• Gut
• Brain
• Insulin
• Liraglutide
• Alzheimer disease
• Neuroprotection