glucagon-like-peptide-1 and Memory-Disorders

DPP-4 inhibitors have been shown to reverse amyloid deposition in Alzheimer's disease (AD) patients with cognitive impairment. Ocimum sanctum L. leaves reported the presence of important phytoconstituents which are reported to have DPP-4 inhibitory activity. To investigate the effects of petroleum ether extract of Ocimum sanctum L. (PEOS) in Intracerebroventricular streptozotocin (ICV-STZ) induced AD rats. ICV-STZ (3 mg/kg) was injected bilaterally into male Wistar rats, while sham animals received the artificial CSF. The ICV-STZ-induced rats were administered with three doses of PEOS (100, 200, and 400 mg/kg, p.o.) for thirty days. All experimental rats were subjected to behaviour parameters (radial arm maze task and novel object recognition test), neurochemical parameters such as GLP-1, Aβ42, and TNF-α levels, and histopathological examination (Congo red staining) of the left brain hemisphere. PEOS significantly reversed the spatial learning and memory deficit exhibited by ICV-STZ-induced rats. Furthermore, PEOS also shows promising results in retreating Aβ deposition, TNF α, and increasing GLP-1 levels. The histopathological study also showed a significant dose-dependent reduction in amyloid plaque formation and dense granule in PEOS -treated rats as compared to the ICV-STZ induced rats (Negative control). The results show that extract of Ocimum sanctum L. attenuated ICV-STZ-induced learning and memory deficits in rats and has the potential to be employed in the therapy of AD.

Topics: Alzheimer Disease; Animals; Cognitive Dysfunction; Congo Red; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Glucagon-Like Peptide 1; Inflammation; Male; Maze Learning; Memory Disorders; Ocimum sanctum; Plant Extracts; Rats; Rats, Wistar; Streptozocin; Tumor Necrosis Factor-alpha

Growing evidences indicate that neuropathic pain is frequently accompanied with cognitive impairments, which aggravate the decrease in the quality of life of chronic pain patients. Furthermore, it has been shown that the activation of Glucagon-like-peptide-1receptor (GLP-1R) improved memory deficit in multiple diseases, including Alzheimer's disease (AD), stroke. However, whether GLP-1R activation could improve memory impairment induced by neuropathic pain and the mechanisms underlying the effect of the activation of GLP-1R on memory protection have not yet been established. The spared nerve injury (SNI) model was established as a kind of neuropathic pain. And novel-object recognition memory (hippocampus-dependent memory) was tested by the novel object recognition test (NORT). The expression levels of GLP-1, GLP-1R, adenosine monophosphate-activated protein kinase (AMPK), p-AMPKThr172, nuclear factor κ B p65 (NF-κB p65), interleukin-1beta (IL-1β), IL-1β p17 (mature IL-1β), tumor necrosis factor-alpha (TNF-α) and the synaptic proteins were tested in the murine hippocampus with memory deficits caused by neuropathic pain. Then, exenatide acetate (Ex-4, a GLP-1R agonist), exendin (9-39) (Ex(9-39), a GLP-1R antagonist) and Compound C dihydrochloride (CC, an AMPK inhibitor) were used to test the effects of the activation of GLP-1R in the mice with neuropathic pain. First, we uncovered that neuropathic pain could inhibit GLP-1/GLP-R axis, disturb inflammatory signaling pathway, increase the expression of IL-1β, IL-1β p17 and TNF-α, downregulate the synaptic proteins (postsynaptic density protein 95 (PSD95) and Arc). Subsequently, we reported that Ex-4 treatment could improve recognition memory impairment, increase the ratio of p-AMPKThr172/AMPK, inhibit the phosphorylation NF-κB p65 and decrease the expression of IL-1β, IL-1β p17 and TNF-α, upregulate the levels of PSD95 and Arc. Moreover, we found that Ex(9-39) and CC treatment could abrogate the memory protection of activation of GLP-1R in mice with neuropathic pain. The results indicated that the activation of GLP-1R could improve recognition memory impairment via regulating AMPK/NF-κB pathway, improving neuroinflammation, reversing the decreased level of synaptic proteins in neuropathic pain mice.

Topics: AMP-Activated Protein Kinase Kinases; Animals; Chronic Pain; Disease Models, Animal; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hippocampus; Interleukin-1beta; Memory Disorders; Mice; Neuralgia; Neuroinflammatory Diseases; Open Field Test; Peptide Fragments; Peripheral Nerve Injuries; Recognition, Psychology; Sciatic Nerve; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Behavior, Animal; Brain; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus, Type 2; Estradiol; Female; Glucagon-Like Peptide 1; Glycolysis; Hypoglycemic Agents; Inflammation; Liraglutide; Maze Learning; Memory Disorders; Mice; Neurofibrillary Tangles; Nitrosative Stress; Oxidative Stress; Peptide Fragments; Phenotype; Plaque, Amyloid

Glucagon-like peptide-1 (GLP-1) signaling in the brain plays an important role in the regulation of glucose metabolism, which is impaired in Alzheimer's disease (AD). Here, we detected the GLP-1 and GLP-1 receptor (GLP-1R) in AD human brain and APP/PS1/Tau transgenic (3xTg) mice brain, finding that they were both decreased in AD human and mice brain. Enhanced GLP-1 exerts its protective effects on AD, however, this is rapidly degraded into inactivated metabolites by dipeptidyl peptidase-4 (DPP-4), resulting in its extremely short half-time. DPP-4 inhibitors, thus, was applied to improve the level of GLP-1 and GLP-1R expression in the hippocampus and cortex of AD mice brains. It is also protected learning and memory and synaptic proteins, increased the O-Glycosylation and decreased abnormal phosphorylation of tau and neurofilaments (NFs), degraded intercellular β-amyloid (Aβ) accumulation and alleviated neurodegeneration related to GLP-1 signaling pathway.

Topics: Adamantane; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cerebral Cortex; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycosylation; Hippocampus; Humans; Intermediate Filaments; Learning; Memory Disorders; Mice; Mice, Transgenic; Nerve Degeneration; Phosphorylation; Signal Transduction; Sitagliptin Phosphate; tau Proteins

Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer disease (AD). Previous studies have shown that the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) that have anti-diabetic properties show very promising effects in animal models of AD. Glucagon (Gcg) is a hormone and growth-factor, and the Gcg receptor is expressed in the brain. Here we test the effects of a triple receptor agonist (TA), which activates GIP-1, GIP and glucagon receptors at the same time. In the present study, the effects of the TA were evaluated in the APP/PS1 transgenic mouse model of AD. The TA was injected once-daily (10 nmol/kg i.p.) for two months. The results showed that treatment with TA significantly reversed the memory deficit in the APP/PS1 mice in a spatial water maze test. Moreover, the drug reduced levels of the mitochondrial pro-apoptotic signaling molecule BAX, increased the anti-apoptotic signaling molecule Bcl-2 and enhanced the levels of BDNF, a key growth factor that protects synaptic function. Levels of synaptophysin were enhanced, demonstrating protection from synaptic loss that is observed in AD. Neurogenesis in the dentate gyrus was furthermore enhanced as shown in the increase of doublecortin positive cells. Furthermore, TA treatment reduced the total amount of β-amyloid, reduced neuroinflammation (activated microglia and astrocytes), and oxidative stress in the cortex and hippocampus. Thus, these findings show that novel TAs are a promising lead for the design of future treatment strategies in AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hippocampus; Memory Disorders; Mice; Mice, Transgenic; Neuroprotective Agents; Plaque, Amyloid; Presenilin-1; Receptors, Gastrointestinal Hormone; Receptors, Glucagon

Insulin resistance and metabolic dysfunction in the brain are considered to be the pathophysiological core of sporadic Alzheimer's disease (sAD). In line with that fact, nutrients that could have therapeutic effects at this level have been investigated as possible targets in AD therapy. Galactose, an epimer of glucose, may serve as an alternative source of energy, and given orally may stimulate secretion of the incretin hormone glucagon-like peptide-1 (GLP-1). Our preliminary research indicated that oral galactose might prevent development of memory impairment in a rat model of sAD generated by intracerebroventricular administration of streptozotocin (STZ-icv). Here, we explored whether chronic oral galactose treatment could have beneficial effects on cognitive deficits already manifested at the time of initiation of galactose treatment in adult STZ-icv rats (treatment initiated 1 month after STZ-icv injection). The results clearly show that a 2-month exposure to oral galactose (200 mg/kg/day administered in a drink ad libitum) normalises impaired learning and memory functions. Memory improvement was accompanied by an improvement in brain glucose hypometabolism measured by

Topics: Administration, Oral; Alzheimer Disease; Animals; Brain; Galactose; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Male; Memory Disorders; Rats; Streptozocin

The anti-obesity drug GLP-1 has been proven to have an impact on central nervous system, while its extremely short half-life greatly limited its use. In this study, our group constructed two engineering strains MG1363-pMG36e-GLP-1 and VNP20009-pLIVE-GLP-1 to continuously express GLP-1, and supplementation of these strains, especially MG1363-pMG36e-GLP-1, had significantly restored the spatial learning and memory impairment of mice caused by LPS (p < 0.05), suppressed glia activation and Aβ accumulation, and downregulated inflammatory expressions of COX-2, TLR-4, TNF-a, and IL-1β. In addition, MG1363-pMG36e-GLP-1 had significantly blocked the translocation of NF-κB signal and inhibited the phosphorylation of redox-sensitive cytoplasmic signalings of MAPKs and PI3K/AKT. These data suggest that MG1363-pMG36e-GLP-1 could be used as a safe and effective nonabsorbed oral treatment for neuroinflammation-related diseases such as Alzheimer's disease (AD).

Topics: Animals; Bacteria; Glucagon-Like Peptide 1; Lipopolysaccharides; Memory Disorders; Mice; Microorganisms, Genetically-Modified

In a recent study, we demonstrated the potential of a cell-penetrating peptide (CPP) penetratin to deliver the peptide drug insulin to the brain via nasal administration, and its pharmacological effect on the mild cognitive dysfunction in senescence-accelerated mouse (SAMP8). However, the therapeutic potential of intranasal insulin administration was attenuated when applied to the aged SAMP8 with severe cognitive dysfunction. The present study, therefore, aimed to overcome the difficulty in treating severe cognitive dysfunction using insulin by investigating potential alternatives, glucagon-like peptide-1 (GLP-1) receptor agonists such as exendin-4. Examination using normal ddY mice demonstrated that the distribution of exendin-4 throughout the brain was dramatically increased by intranasal coadministration with the L-form of penetratin. The activation of hippocampal insulin signaling after the simultaneous nose-to-brain delivery of exendin-4 and an adequate level of insulin were confirmed by analyzing the phosphorylation of Akt. Furthermore, spatial learning ability, evaluated in the Morris water maze test after daily administration of exendin-4 with L-penetratin and supplemental insulin for 4 weeks, suggested therapeutic efficacy against severe cognitive dysfunction. The present study suggests that nose-to-brain delivery of exendin-4 with supplemental insulin, mediated by CPP coadministration, shows promise for the treatment of progressive cognitive dysfunction in SAMP8.

Topics: Administration, Intranasal; Amyloid beta-Peptides; Animals; Brain; Cell-Penetrating Peptides; Cognitive Dysfunction; Drug Carriers; Exenatide; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin; Male; Memory Disorders; Mice; Signal Transduction

Although amyloid β protein (Aβ) has been recognized as one of the main pathological characteristics in the brain of Alzheimer's disease (AD), the effective strategies against Aβ neurotoxicity are still deficient up to now. Glucagon-like peptide 1 (GLP-1), a natural gut hormone, was found to be effective in modulating insulin signaling and neural protection, but short half-life limited its clinical application in AD treatment. CJC-1131, a newly designed GLP-1 analogue with very longer half-life, has shown good effectiveness in the treatment of type 2 diabetes mellitus (T2DM). However, it is unclear whether CJC-1131 could alleviate Aβ-induced neurotoxicity in cognitive behavior and electrophysiological property. The present study investigated the effects of CJC-1131 on the Aβ-induced impairments in spatial memory and synaptic plasticity of rats by using Morris water maze test and in vivo field potential recording. The results showed that Aβ1-42-induced increase in the escape latency of rats in hidden platform test and decrease in swimming time percent in target quadrant were effectively reversed by CJC-1131 pretreatment. Further, CJC-1131 prevented against Aβ1-42-induced suppression of hippocampal long term potentiation (LTP). In addition, Aβ1-42 injection resulted in a significant decrease of p-PKA in the hippocampus, which was effectively prevented by CJC-1131 treatment. These results indicated that CJC-1131 protected the cognitive function and synaptic plasticity of rats against Aβ-induced impairments, suggesting that GLP-1 analogue CJC-1131 might be potentially beneficial to the prevention and treatment of AD, especially those with T2DM or blood glucose abnormality.

Topics: Amyloid beta-Peptides; Animals; Electrophysiological Phenomena; Glucagon-Like Peptide 1; Hippocampus; Long-Term Potentiation; Male; Maleimides; Memory Disorders; Neuronal Plasticity; Neuroprotective Agents; Peptides; Rats; Rats, Sprague-Dawley; Spatial Memory

BACKGROUND Glucagon-like peptide-1 (GLP-1) has been reported to exert some beneficial effects on the central nervous system (CNS). However, the effect of GLP-1 on cognitive impairment associated with type 2 diabetes is not well known. This study investigated the effect of GLP-1 on ameliorating memory deficits in type 2 diabetic rats. MATERIAL AND METHODS Type 2 diabetic rats were induced by a high-sugar, high-fat diet, followed by streptozotocin (STZ) injection and then tested in the Morris Water Maze (MWM) 1 week after the induction of diabetes. The mRNA expression of Arc, APP, BACE1, and PS1 were determined by real-time quantitative PCR, and the Arc protein was analyzed by immunoblotting and immunohistochemistry. RESULTS Type 2 diabetic rats exhibited a significant decline in learning and memory in the MWM tests, but GLP-1 treatment was able to protect this decline and significantly improved learning ability and memory. The mRNA expression assays showed that GLP-1 treatment markedly reduced Arc, APP, BACE1, and PS1 expressions, which were elevated in the diabetic rats. Immunoblotting and immunohistochemistry results also confirmed that Arc protein increased in the hippocampus of diabetic rats, but was reduced after GLP-1 treatment. CONCLUSIONS Our findings suggest that GLP-1 treatment improves learning and memory deficits in type 2 diabetic rats, and this effect is likely through the reduction of Arc expression in the hippocampus.

Topics: Animals; Blood Glucose; Cognitive Dysfunction; Cytoskeletal Proteins; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Glucagon-Like Peptide 1; Hippocampus; Male; Maze Learning; Memory Disorders; Nerve Tissue Proteins; Rats; Rats, Sprague-Dawley

Several single incretin receptor agonists that are approved for the treatment of type 2 diabetes mellitus (T2DM) have been shown to be neuroprotective in cell and animal models of neurodegeneration. Recently, a synthetic dual incretin receptor agonist, nicknamed "twincretin," was shown to improve upon the metabolic benefits of single receptor agonists in mouse and monkey models of T2DM. In the current study, the neuroprotective effects of twincretin are probed in cell and mouse models of mild traumatic brain injury (mTBI), a prevalent cause of neurodegeneration in toddlers, teenagers and the elderly. Twincretin is herein shown to have activity at two different receptors, dose-dependently increase levels of intermediates in the neurotrophic CREB pathway and enhance viability of human neuroblastoma cells exposed to toxic concentrations of glutamate and hydrogen peroxide, insults mimicking the inflammatory conditions in the brain post-mTBI. Additionally, twincretin is shown to improve upon the neurotrophic effects of single incretin receptor agonists in these same cells. Finally, a clinically translatable dose of twincretin, when administered post-mTBI, is shown to fully restore the visual and spatial memory deficits induced by mTBI, as evaluated in a mouse model of weight drop close head injury. These results establish twincretin as a novel neuroprotective agent and suggest that it may improve upon the effects of the single incretin receptor agonists via dual agonism.

Topics: Animals; Body Temperature; Brain Injuries, Traumatic; Cell Line, Tumor; Cells, Cultured; CREB-Binding Protein; Disease Models, Animal; Embryo, Mammalian; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred ICR; Neuroblastoma; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptors, Gastrointestinal Hormone; Recognition, Psychology; Signal Transduction

Type 2 diabetes is a risk factor in the development of Alzheimer's disease (AD). It has been shown that insulin signalling is desensitised in the brains of AD patients. The incretin hormone Glucagon-like peptide-1 (GLP-1) facilitates insulin signalling, and long-lasting analogues such as liraglutide (Victoza(®)) are on the market as type 2 diabetes treatments. We have previously shown that liraglutide improved cognitive function, reduced amyloid plaque deposition, inflammation, overall APP and oligomer levels and enhanced LTP when injected peripherally for two months in 7 month old APPswe/PS1ΔE9 (APP/PS1) mice. This showed that liraglutide has preventive effects at the early stage of AD development. The current study investigated whether Liraglutide would have restorative effects in late-stage Alzheimer's disease in mice. Accordingly, 14-month-old APP/PS1 and littermate control mice were injected with Liraglutide (25 nmol/kg bw) ip. for 2 months. Spatial memory was improved by Liraglutide-treatment in APP/PS1 mice compared with APP/PS1 saline-treated mice. Overall plaque load was reduced by 33%, and inflammation reduced by 30%, while neuronal progenitor cell count in the dentate gyrus was increased by 50%. LTP was significantly enhanced in APP/PS1 liraglutide-treated mice compared with APP/PS1 saline mice, corroborated with increased synapse numbers in hippocampus and cortex. Total brain APP and beta-amyloid oligomer levels were reduced in Liraglutide-treated APP/PS1 mice while IDE levels were increased. These results demonstrate that Liraglutide not only has preventive properties, but also can reverse some of the key pathological hallmarks of AD. Liraglutide is now being tested in clinical trials in AD patients. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cell Count; Disease Models, Animal; Glucagon-Like Peptide 1; Inflammation; Liraglutide; Long-Term Potentiation; Male; Memory; Memory Disorders; Mice; Mice, Transgenic; Nerve Degeneration; Neuroprotective Agents; Plaque, Amyloid; Stem Cells; Synapses

The aim of this study was to investigate the effect of liraglutide on Alzheimer-like learning and memory impairment in mice, which were intracerebroventricularly (i.c.v.) injected with streptozotocin (STZ). Twenty-four mice were randomly divided into three groups: control (CON), AD model (STZ), and liraglutide-treated (LIR). The results show that both hyperphosphorylated tau and neurofilament proteins had deceased protein glycosylation and the tau bound to microtubules was lower in the STZ group compared to the CON group. The expression of JNK phosphorylation was higher and the number of Fluoro-Jade-B-positive degenerative neurons was increased in the STZ group as compared to both the CON and liraglutide groups. Escape latency in the STZ group was longer than that in both the CON and LIR groups, while the number of hidden platform crossings in path length was less than that in the other two groups. Liraglutide decreased the hyperphosphorylation levels of tau and neurofilament proteins, increased protein O-glycosylation, increased tau bound to microtubules, and also significantly improved the learning and memory ability of the mice. These results suggest that the effects of liraglutide on decreasing the hyperphosphorylation of tau and neurofilament proteins by enhancing O-glycosylation of neuronal cytoskeleton protein, improving the JNK and ERK signaling pathway, and reducing neural degeneration may be related to its protective effects on AD-like learning and memory impairment induced by i.c.v. injection of STZ. Our results indicate that GLP-1 analogs represent a novel treatment strategy for Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Diabetes Mellitus, Experimental; Glucagon-Like Peptide 1; Hypoglycemic Agents; Injections, Intraventricular; Insulin; Liraglutide; Male; Maze Learning; Memory Disorders; Mice; Neurofilament Proteins; Neuroprotective Agents; Phosphorylation; Random Allocation; Signal Transduction; tau Proteins

Traumatic brain injury (TBI) is a global problem reaching near epidemic numbers that manifests clinically with cognitive problems that decades later may result in dementias like Alzheimer's disease (AD). Presently, little can be done to prevent ensuing neurological dysfunctions by pharmacological means. Recently, it has become apparent that several CNS diseases share common terminal features of neuronal cell death. The effects of exendin-4 (Ex-4), a neuroprotective agent delivered via a subcutaneous micro-osmotic pump, were examined in the setting of mild TBI (mTBI). Utilizing a model of mTBI, where cognitive disturbances occur over time, animals were subjected to four treatments: sham; Ex-4; mTBI and Ex-4/mTBI. mTBI mice displayed deficits in novel object recognition, while Ex-4/mTBI mice performed similar to sham. Hippocampal gene expression, assessed by gene array methods, showed significant differences with little overlap in co-regulated genes between groups. Importantly, changes in gene expression induced by mTBI, including genes associated with AD were largely prevented by Ex-4. These data suggest a strong beneficial action of Ex-4 in managing secondary events induced by a traumatic brain injury.

Topics: Alzheimer Disease; Animals; Behavior, Animal; Brain Injuries; Cognition; Computational Biology; DNA, Complementary; Exenatide; Gene Expression; Glucagon-Like Peptide 1; Hippocampus; Male; Memory Disorders; Mice; Mice, Inbred ICR; Neuroprotective Agents; Peptides; Real-Time Polymerase Chain Reaction; Recognition, Psychology; RNA; Signal Transduction; Venoms

Glucagon-like peptide-1 (GLP-1) is an endogenous intestinal peptide that enhances glucose-stimulated insulin secretion. Its natural cleavage product GLP-1(9-36)(amide) possesses distinct properties and does not affect insulin secretion. Here we report that pretreatment of hippocampal slices with GLP-1(9-36)(amide) prevented impaired long-term potentiation (LTP) and enhanced long-term depression induced by exogenous amyloid β peptide Aβ((1-42)). Similarly, hippocampal LTP impairments in amyloid precursor protein/presenilin 1 (APP/PS1) mutant mice that model Alzheimer's disease (AD) were prevented by GLP-1(9-36)(amide). In addition, treatment of APP/PS1 mice with GLP-1(9-36)(amide) at an age at which they display impaired spatial and contextual fear memory resulted in a reversal of their memory defects. At the molecular level, GLP-1(9-36)(amide) reduced elevated levels of mitochondrial-derived reactive oxygen species and restored dysregulated Akt-glycogen synthase kinase-3β signaling in the hippocampus of APP/PS1 mice. Our findings suggest that GLP-1(9-36)(amide) treatment may have therapeutic potential for AD and other diseases associated with cognitive dysfunction.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Association Learning; CA3 Region, Hippocampal; Disease Models, Animal; Drug Evaluation, Preclinical; Excitatory Postsynaptic Potentials; Fear; Female; Glucagon-Like Peptide 1; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Male; Memory Disorders; Mice; Mice, Transgenic; Mitochondria; Neuronal Plasticity; Nootropic Agents; Organophosphorus Compounds; Peptide Fragments; Peptides; Presenilin-1; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction; Ubiquinone

We tested here the impact of a long-term inhibition of dipeptidyl peptidase-4 (DPP-4) with sitagliptin on the deposition of amyloid-beta within the brain and deficits in memory-related behavioral paradigms in a model of Alzheimer's disease (AD): double transgenic mice B6*Cg-Tg(APPswe,PSEN1dE9)85Dbo/J. Mice began to receive sitagliptin at 7 months of age. Three different dose of sitagliptin (5, 10 and 20 mg/kg), were administered daily for 12 weeks by gastric gavage. The treatments counteracted: (i) the memory impairment in the contextual fear conditioning test; (ii) increased the brain levels of GLP-1; (iii) produced significant reductions of nitrosative stress and inflammation hallmarks within the brain, as well as (iv) a significant diminution in the ultimate number and total area of betaAPP and Abeta deposits. All these effects much more evident for the dose of 20 mg/kg sitagliptin. The long-term inhibition of the endogenous DPP-4 enzymes with sitagliptin can significantly delay some forms of AD pathology, including amyloid deposition, when administered early in the disease course of a transgenic mouse model of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Memory Disorders; Mice; Mice, Transgenic; Motor Activity; Pyrazines; Sitagliptin Phosphate; Triazoles

Previous studies in children with diabetes found that hyperglycemia induces memory dysfunction. In this study, we investigated memory and synaptic plasticity in streptozotocine (STZ)-induced diabetic rats during the juvenile period. We further investigated the effects of glucagon-like peptide-1 (GLP-1) on the diabetes-induced profiles. STZ (85 mg/kg, i.p.) was administered to 17-day-old Wistar rats to induce type-1 juvenile diabetes mellitus (JDM). In the Y-maze test, JDM rats showed significant impairment of learning and memory, which were improved by GLP-1 (7-36) amide (1 microg/5 microl/rat, i.c.v.). Extracellular recording at Schaffer collateral synapses in the CA1 region of hippocampal slices showed that long-term potentiation and paired-pulse facilitation in JDM rats were similar to age-matched control rats. However, the input-output relation was strengthened, and long-term depression (LTD) and responses of N-methyl d-aspartic acid through NR2B subunits were weakened in the JDM rats. GLP-1 (7-36) amide (100 nM) increased the magnitude of LTD and the responses through NR2B in the JDM rats. These results indicate that the lack of LTD and NR2B responses may contribute to impairment of memory associated with JDM, suggesting the potential usefulness of GLP-1 in the treatment of memory dysfunction in JDM.

Topics: Animals; Diabetes Mellitus, Experimental; Excitatory Postsynaptic Potentials; Female; Glucagon-Like Peptide 1; Hippocampus; Hyperglycemia; In Vitro Techniques; Long-Term Synaptic Depression; Male; Maze Learning; Memory Disorders; N-Methylaspartate; Neuronal Plasticity; Peptide Fragments; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Streptozocin; Synaptic Transmission

We examined the effects of continuous infusion of exendin (5-39), an antagonist of glucagon-like peptide-1 (GLP-1) receptors, into the rat brain using a mini-osmotic pump on beta-amyloid protein-induced amnesia and apoptosis. Co-infusion of exendin (5-39) with beta-amyloid protein (1-40) prevented the memory impairment and DNA fragmentation in the hippocampal CA1 region observed with infusion of beta-amyloid protein alone. These results indicated a functional role of endogenous GLP-1 in beta-amyloid protein-induced neurotoxicity.

Topics: Amyloid beta-Peptides; Animals; Cell Death; DNA Fragmentation; Drug Combinations; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hippocampus; Male; Memory; Memory Disorders; Neurons; Peptide Fragments; Protein Precursors; Rats; Rats, Wistar; Receptors, Glucagon

We examined the relationship between the histochemical distribution of endogenous GLP-1 (7-36) amide in the hippocampus and memory impairment assessed by a step-through type passive avoidance task in rats continuously infused with beta-amyloid protein (1-40) into the lateral cerebroventricle using a mini-osmotic pump. Our results demonstrated that endogenous GLP-1 (7-36) amide appears in the hippocampus accompanied by progression of memory impairment. Electrophysiological studies also indicated that endogenous GLP-1 inhibits hippocampal neuronal activity in beta-amyloid protein-treated rats.

Topics: Amyloid beta-Peptides; Animals; Avoidance Learning; Brain Chemistry; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hippocampus; Immunohistochemistry; Injections, Intraventricular; Lateral Ventricles; Male; Memory Disorders; Peptide Fragments; Protein Precursors; Rats; Rats, Wistar; Receptors, Glucagon