title: Metformin attenuates Alzheimer's disease-like neuropathology in obese, leptin-resistant mice.
abstract: Diabetes increases the risk of Alzheimer's disease (AD). The pathological hallmarks for AD brains are extracellular amyloid plaques formed by β-amyloid peptide (Aβ) and intracellular neurofibrillary tangles consisting of hyperphosphorylated tau protein. This study was designed to determine AD-like brain changes in mice modeling for type 2 diabetes. The effects of metformin on these changes also were studied. Seven-week old male db/db mice received intraperitoneal injection of 200 mg kg⁻¹ d⁻¹ metformin for 18 weeks. They were subjected to Barnes maze at an age of 21 weeks and fear conditioning at an age of 24 weeks to assess their cognitive functions. Hippocampus was harvested after these tests for biochemical evaluation. The db/db mice had more tau phosphorylated at S396 and total tau in their hippocampi than their non-diabetic control db+mice. Activated/phosphorylated c-jun N-terminal kinase (JNK), a tau kinase, was increased in the db/db mouse hippocampus. Metformin attenuated the increase of total tau, phospho-tau and activated JNK. The db/db mice had increased Aβ levels. Metformin attenuated the reduction of synaptophysin, a synaptic protein, in the db/db mouse hippocampus. Metformin did not attenuate the impairments of spatial learning and memory as well as long-term hyperglycemia in the db/db mice. Our results suggest that the db/db mice have multiple AD-like brain changes including impaired cognitive functions, increased phospho-tau and Aβ as well as decreased synaptic proteins. Activation of JNK may contribute to the increased phospho-tau in the db/db mice. Metformin attenuates AD-like biochemical changes in the brain of these mice.
authors.affiliation: Department of Anesthesiology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Jiejie
authors.initials: J
authors.lastname: Li
authors.forename: Jiao
authors.initials: J
authors.lastname: Deng
authors.forename: Wenli
authors.initials: W
authors.lastname: Sheng
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Zuo
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D003213:Conditioning, Psychological / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000523:psychology; D004195:Disease Models, Animal; D004351:Drug Resistance; D005239:Fear / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008820:Mice, Obese; D016874:Neurofibrillary Tangles / Q000187:drug effects / Q000473:pathology; D010766:Phosphorylation; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000473:pathology; D054648:Protein Phosphatase 2 / Q000378:metabolism; D016708:Synaptophysin; D033921:Vesicular Transport Proteins / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D007004:Hypoglycemic Agents; D020738:Leptin; D016708:Synaptophysin; C569015:Syp protein, mouse; D033921:Vesicular Transport Proteins; D016875:tau Proteins; D008687:Metformin; D048031:JNK Mitogen-Activated Protein Kinases; D054648:Protein Phosphatase 2