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The role of endogenous glucagon-like peptide 1 and gastric inhibitory polypeptide in neurodegeneration
Croatia (CroMSIC) - University of Zagreb, Zagreb
Department of Pharmacology
Jan Homolak, Ana Babić Perhoč, Ana Knezović, Jelena Osmanović Barilar, Melita Šalković Petrišić
Type of Research Project
- Basic science
What is the background of the project?
Metabolic dysfunction is currently being investigated as one of the key etiopathogenetic factors in neurodegeneration. Peripheral insulin resistance has been identified as a risk factor for Alzheimer's disease (AD) and Parkinson's disease (PD), and biochemical studies reported desensitized insulin signaling in the brains of AD/PD patients. Based on the molecular similarities of insulin resistance and neurodegeneration, drugs originally developed for treatment of type 2 diabetes mellitus (T2DM) are currently being investigated in the context of neurodegeneration. Incretin mimetics are particularly interesting as incretins are synthetized in the brain where they act as neuropeptides with neuroprotective, anti- inflammatory, and neurotrophic properties. Although exogenous glucagon-like peptide-1 (GLP-1) mimetics are currently being tested in AD/PD clinical trials, neuroprotective effects of endogenous incretins and their therapeutic potential in neurodegeneration is yet to be elucidated. Our previous research in the streptozotocin- induced rat model of sporadic Alzheimer's disease (sAD) has shown that oral galactose induces GLP-1 secretion and prevents and ameliorates previously developed cognitive impairment in the early stage of sAD pathology.
What is the aim of the project?
General aim of the project is understanding the interaction of galactose with incretin system in models of Alzheimer’s and Parkinson’s disease. More specific baseline aims of the project are: understanding the physiological response to oral galactose treatment, understanding the brain and brain-gut effects of two incretin hormones, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), and elucidating short-term and long-term nutrient-incretin interaction at the level of intestinal nutrient absorption and incretin signaling.
What techniques and methods are used?
Two animal models will be used in the research: rat model of sporadic Alzheimer’s disease based on intracerebroventricular administration of streptozotocin and rat model of Parkinson’s disease based on intrastriatal administration of 6-hydroxydopamine (interaction with animals will be in concordance with national and international legislation and follow all ethical standards). Robust behavioral analysis of animals will be done by means of tests for cognition, anxiety, motor activity, etc. Several biochemical techniques based on enzymatic changes, extraction or electrochemical interference of molecules will be used for tissue analysis of brain, duodenum, ileum, plasma and cerebrospinal fluid of animals. Additionaly, levels of small molecules of interest (GLP-1, GIP, insulin,...) will be examined by ELISA, and expression of proteins of interest and key signaling molecules by immunofluorescence, and proteomic techniques (eg. Western blot). Metabolic changes in vivo will be monitored by positron emission tomography.
What is the role of the student?
- The tasks of the student will be performed on his/her own
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
Animal tissue sample preparation by formalin fixation and paraffin embedding followed by microtome sectioning and slide mounting or cryopreservation and cryostat sectioning. Histological staining, immunohistochemical and immunofluorescent staining (single staining and coexpression studies) followed by epifluorescence microscopy and subsequent computational image analysis (spectral analysis, colocalisation densitometry, morphometric computational techniques,...). Preparation of liquid nitrogen frozen tissue by lysis buffer sonication, protein extraction, protein measurement, SDS-polyacrilamide gel electrophoresis, dry, semi-dry and wet protein transfer, membrane fixation, nitrocellulose immunoblotting, enhanced chemiluminiscence protein visualization, computational densitometry, band analyis and quantification. Tissue homogenate biochemical assays (eg. TBA- MDA, DTNB-based sulfhydryl quantification, redox titrations, inhibition of 1,2,3-trihydroxybenzene autooxidation). Electrochemical techniques based on closed system redox coupled oxidation-reduction potential measurements. ELISA and enzymatic techniques for precise quantification of small molecules. Ex vivo pharmacological studies in tissue baths with subsequent molecular analyses. Computational analysis of behavioral experiments by means of manual, semi-automatic and unsupervised learning analyses of object preference, anxiety-related behavior, locomotor and social behavioral changes, homecage monitoring, neural signal processing. The student and mentor will work together to design a specific feasible research project during the stay in the laboratory. Based on the chosen research question the student will be introduced to specific molecular, analytical, computational and other methods to answer the question.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
Theoretical teaching will be flexible and focused on the specific knowledge needed to understand the results of the molecular techniques used during the experiment. It will be provided by the tutors.
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student will prepare a presentation - The student’s name will be mentioned in a future publication
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
Experience in the laboratory work or any kind of research is a big advantage because of the short duration of the exchange. Prior understanding of immunochemical techniques, western blot, animal behavioral analysis or statistics as well. Previous experience with: laboratory work or research involvement or programming or statistics.
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts: - Medical students - Graduated students (less than 6 months) - Pre-Medical students from the American-British system - Students in biomedical fields
- Osmanovic Barilar J.; Knezovic A.; Babic Perhoc A.; Homolak J.; Riederer P.; Salkovic-Petrisic M. Shared cerebral metabolic pathology in non-transgenic animal models of Alzheimer's and Parkinson's disease J.Neural Transm (2020)
- Babic Perhoc A; Osmanovic Barilar J; Knezovic A; Farkas V; Bagaric R; Svarc A; Grünblatt E; Riederer P; Salkovic-Petrisic M. Cognitive; behavioral and metabolic effects of oral galactose treatment in the transgenic Tg2576 mice. Neuropharmacology. 2019 Apr;148:50-67. doi: 10.1016/j.neuropharm.2018.12.018. Epub 2018 Dec 17. PubMed PMID: 30571958.
- Knezovic A; Osmanovic Barilar J; Babic A; Bagaric R; Farkas V; Riederer P; Salkovic-Petrisic M. Glucagon-like peptide-1 mediates effects of oral galactose in streptozotocin-induced rat model of sporadic Alzheimer's disease. Neuropharmacology. 2018 Jun;135:48-62. doi: 10.1016/j.neuropharm.2018.02.027. Epub 2018 Feb 28. PubMed PMID: 29501615.
- Riederer P; Korczyn AD; Ali SS; Bajenaru O; Choi MS; Chopp M; Dermanovic-Dobrota V; Grünblatt E; Jellinger KA; Kamal MA; Kamal W; Leszek J; Sheldrick-Michel TM; Mushtaq G; Meglic B; Natovich R; Pirtosek Z; Rakusa M; Salkovic-Petrisic M; Schmidt R; Schmitt A; Sridhar GR; Vécsei L; Wojszel ZB; Yaman H; Zhang ZG; Cukierman-Yaffe T. The diabetic brain and cognition. J Neural Transm (Vienna). 2017 Nov;124(11):1431-1454. doi: 10.1007/s00702-017-1763-2. Epub 2017 Aug 1. Review. PubMed PMID: 28766040.
- Knezovic A; Loncar A; Homolak J; Smailovic U; Osmanovic Barilar J; Ganoci L; Bozina N; Riederer P; Salkovic-Petrisic M. Rat brain glucose transporter-2; insulin receptor and glial expression are acute targets of intracerebroventricular streptozotocin: risk factors for sporadic Alzheimer's disease? J Neural Transm (Vienna). 2017 Jun;124(6):695-708. doi: 10.1007/s00702-017-1727-6. Epub 2017 May 3. PubMed PMID: 28470423.
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