Catalog Number: I001221
Strain Name: C57BL/6Cya-Mapttm1(hMAPT)Glp1rtm1(hGLP1R)/Cya
Genetic Background: C57BL/6Cya
Strain Description
The tau protein, a microtubule-associated protein encoded by MAPT is primarily localized to neuronal axons and plays a critical role in microtubule stability and assembly. By binding to microtubules, tau protein helps to maintain neuronal cell shape. Mutations in MAPT can promote tau aggregation, leading to pathological tau protein accumulation and death of glutamatergic cortical neurons [1]. Additionally, certain MAPT mutations can affect pre-mRNA exon splicing, altering the ratio of 3R to 4R tau protein isoforms and increasing the relative production of 4R-tau protein, which is more prone to fibril formation [2].
The GLP-1 receptor (GLP-1R) gene encodes a protein that serves as the receptor for the glucagon-like peptide 1 (GLP-1) hormone, belonging to the glucagon receptor subfamily within the class B G-protein-coupled receptors (GPCRs). G proteins are a class of intracellular signal transduction proteins typically associated with seven-transmembrane receptors (GPCRs). When a GPCR binds to its ligand, it activates the G protein, causing it to dissociate from the Gβγ subunit and initiate downstream effects through interactions with membrane-bound effector molecules. This signaling process is known as canonical G protein signaling. GLP-1R is a multi-transmembrane protein characterized by a typical seven-transmembrane core domain and a relatively large extracellular domain, which can stimulate glucose-induced insulin secretion [3]. GLP-1R is a cell surface receptor protein widely expressed in tissues such as the brain, small intestine, heart, and lungs. It internalizes in response to GLP-1 and GLP-1 analogs and plays a crucial role in the insulin secretion signaling cascade. Additionally, data from animal models indicate its neuroprotective effects [4-5]. Polymorphisms of this gene are closely associated with diabetes. The GLP1R protein is an important drug target for treating type 2 diabetes and stroke. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a new class of antidiabetic drugs in recent years. They activate GLP1R to enhance insulin secretion, suppress glucagon secretion, delay gastric emptying, and reduce food intake through central appetite suppression, lowering blood glucose and weight loss [6].
The B6-htau/hGLP-1R mouse is obtained by mating B6-htau mice (Catalog No.: C001410) with B6-hGLP-1R mice (Catalog No.: C001421). This model can be used for research on neurodegenerative diseases such as frontotemporal dementia (FTD) and Alzheimer's disease (AD), as well as metabolic diseases such as obesity and type 2 diabetes. It is also useful for developing GLP-1 receptor agonist (GLP-1RA) drugs or for the preclinical evaluation of the potential therapeutic effects of GLP-1RA drugs in tauopathy-related diseases like Alzheimer's disease (AD).
Strain Strategy
Obtained by mating B6-htau mice (Catalog No.: C001410) with B6-hGLP-1R mice (Catalog No.: C001421).
Application
References
[1]trang KH, Golde TE, Giasson BI. MAPT mutations, tauopathy, and mechanisms of neurodegeneration. Lab Invest. 2019 Jul;99(7):912-928.
[2]Lisowiec J, Magner D, Kierzek E, Lenartowicz E, Kierzek R. Structural determinants for alternative splicing regulation of the MAPT pre-mRNA. RNA Biol. 2015;12(3):330-42.
[3]Blad CC, Tang C, Offermanns S. G protein-coupled receptors for energy metabolites as new therapeutic targets. Nat Rev Drug Discov. 2012 Aug;11(8):603-19.
[4]Yun SP, Kam TI, Panicker N, Kim S, Oh Y, Park JS, Kwon SH, Park YJ, Karuppagounder SS, Park H, Kim S, Oh N, Kim NA, Lee S, Brahmachari S, Mao X, Lee JH, Kumar M, An D, Kang SU, Lee Y, Lee KC, Na DH, Kim D, Lee SH, Roschke VV, Liddelow SA, Mari Z, Barres BA, Dawson VL, Lee S, Dawson TM, Ko HS. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease. Nat Med. 2018 Jul;24(7):931-938.
[5]Schonhoff AM, Harms AS. Glial GLP1R: A novel neuroprotector? Mov Disord. 2018 Dec;33(12):1877.
[6]Andreasen CR, Andersen A, Knop FK, Vilsbøll T. Understanding the place for GLP-1RA therapy: Translating guidelines for treatment of type 2 diabetes into everyday clinical practice and patient selection. Diabetes Obes Metab. 2021 Sep;23 Suppl 3:40-52.