oxyntomodulin and Alzheimer-Disease

Semaglutide, a peptidic GLP-1 receptor agonist, has been clinically approved for treatment of type 2 diabetes mellitus and is available in subcutaneous and oral dosage form. Diabetes, insulin resistance, and obesity are responsible for the pathological manifestations of non-alcoholic steatohepatitis (NASH). Similarly, insulin resistance in brain is also responsible for neurodegeneration and impaired cognitive functions.. Observations from phase-3 clinical trials like SUSTAIN and PIONEER indicated anti-obesity potential of semaglutide, which was established in STEP trials. Various pre-clinical and phase-2 studies have indicated the therapeutic potential of semaglutide in non-alcoholic steatohepatitis and neurodegenerative disorders like Parkinson's and Alzheimer's disease.. Significant weight reduction ability of semaglutide has been demonstrated in various phase-3 clinical trials, for which recently semaglutide became the first long-acting GLP-1 receptor agonist to be approved by the United States Food and Drug Administration for management of obesity. Various pre-clinical and clinical studies have revealed the hepatoprotective effect of semaglutide in NASH and neuroprotective effect in Parkinson's and Alzheimer's disease.. Many GLP-1 receptor agonists have shown hepatoprotective and neuroprotective activity in animal and human trials. As semaglutide is an already clinically approved drug, successful human trials would hasten its inclusion into therapeutic treatment of NASH and neurodegenerative diseases. Semaglutide improves insulin resistance, insulin signalling pathway, and reduce body weight which are responsible for prevention or progression of NASH and neurodegenerative diseases.

Topics: Alzheimer Disease; Animals; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Hypoglycemic Agents; Insulin Resistance; Neurodegenerative Diseases; Non-alcoholic Fatty Liver Disease; Obesity; Parkinson Disease

At this time there are no effective methods to alter the disease course in Alzheimer's disease. All FDA approved interventions are for symptomatic relief only. However, it is an exciting time as many agents in development have theorhetical potential to impact the disease course. This review discusses some of the agents that have been in clinical trials, particularly those that affect amyloid processing. Some agents have failed while others still provide hope. Since amyloid is the peptide most closely linked to disease pathogenesis, it is possible that some of the anti-amyloid agents will impact the disease progression in a meaningful way.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal, Humanized; Enzyme Inhibitors; Glucagon-Like Peptides; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Methylene Blue; Nootropic Agents

Semaglutide, a glucagon-like peptide-1 (GLP-1) analogue with an extended half-life of approximately 1 week has being come into clinic trial to treat parkingson's disease but little is known about its effect to prevent against Alzheimer's disease (AD). The goal of the present study was to explore the potential mechanisms of semaglutide to protect against AD.. We treated SH-SY5Y cell line with Aβ. Semaglutide enhanced autophagy by increasing the expression of LC3II, Atg7, Beclin-1 and P62 which were inhibited by Aβ. Our results provide a clue for the hypothesis that autophagy enhancement and apoptosis inhibition may be involved in the effect of semaglutide to protect against Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Apoptosis; Autophagy; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Glucagon-Like Peptides; Humans; Neuroprotective Agents; Peptide Fragments

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cognition; Cognitive Dysfunction; Gene Expression Regulation; Glucagon-Like Peptides; Hippocampus; Histone-Lysine N-Methyltransferase; Histones; Inflammation; Male; Mice; NF-E2-Related Factor 2; Oxidative Stress; Quinazolines

Dulaglutide, a novel long-acting glucagon-like peptide 1 (GLP-1) receptor agonist, is an incretin mimetic approved for type 2 diabetes mellitus (T2DM) treatment. Alzheimer's disease (AD) is called type 3 diabetes. The aim of this study is to explore the effects of dulaglutide on the learning and memory impairment in AD mice induced by injection of streptozocin (STZ) via intracerebroventricularly (i.c.v.). 32 male C57/BL6 mice were randomly divided into four groups: control group (CON); AD model group (STZ); dulaglutide treated (Dul); dulaglutide and exendin(9-39) (Ex). Western blotting was used to detect the levels of phosphorylated tau, neurofilament (NFs) proteins and phosphorylated PI3K/AKT/GSK3β signaling pathway. Morris water maze (MWM) test was used to assess the spatial learning and memory ability. The results displayed that the hyperphosphorylation of tau and NFs were increased in the STZ and Ex groups compared to the control and Dul groups. Dulaglutide also significantly shortened the escape latency and increased the number of hidden platform crossings in MWM test. The effects of dulaglutide on decreasing the hyperphosphorylation of tau and NFs proteins through improving the PI3K/AKT/GSK3β signaling pathway may be related to its protective effects on impairment of AD-like learning and memory.

Topics: Alzheimer Disease; Animals; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycogen Synthase Kinase 3 beta; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Intermediate Filaments; Male; Maze Learning; Memory; Memory Disorders; Mice, Inbred C57BL; Phosphorylation; Recombinant Fusion Proteins; Signal Transduction; Streptozocin; tau Proteins

Mexican Americans are the fastest aging segment of the U.S. population, yet little scientific literature exists regarding the Alzheimer's disease (AD) among this segment of the population. The extant literature suggests that biomarkers of AD will vary according to race/ethnicity though no prior work has explicitly studied this possibility. The aim of this study was to create a serum-based biomarker profile of AD among Mexican American.. Data were analyzed from 363 Mexican American participants (49 AD and 314 normal controls) enrolled in the Texas Alzheimer's Research & Care Consortium (TARCC). Non-fasting serum samples were analyzed using a luminex-based multi-plex platform. A biomarker profile was generated using random forest analyses.. The biomarker profile of AD among Mexican Americans was different from prior work from non-Hispanic populations with regards to the variable importance plots. In fact, many of the top markers were related to metabolic factors (e.g., FABP, GLP-1, CD40, pancreatic polypeptide, insulin-like-growth factor, and insulin). The biomarker profile was a significant classifier of AD status yielding an area under the receiver operating characteristic curve, sensitivity, and specificity of 0.77, 0.92, and 0.64, respectively. Combining biomarkers with clinical variables yielded a better balance of sensitivity and specificity.. The biomarker profile for AD among Mexican American cases is significantly different from that previously identified among non-Hispanic cases from many large-scale studies. This is the first study to explicitly examine and provide support for blood-based biomarkers of AD among Mexican Americans. Areas for future research are highlighted.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; CD40 Antigens; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Insulin; Male; Mental Status Schedule; Mexican Americans; Middle Aged; Pancreatic Polypeptide; Sensitivity and Specificity; Somatomedins