title: Metformin promotes tau aggregation and exacerbates abnormal behavior in a mouse model of tauopathy.
abstract: BACKGROUND
  Alzheimer disease (AD) and other tauopathies develop cerebral intracellular inclusions of hyperphosphorylated tau. Epidemiological and experimental evidence suggests a clear link between type 2 diabetes mellitus and AD. In AD animal models, tau pathology is exacerbated by metabolic comorbidities, such as insulin resistance and diabetes. Within this context, anitidiabetic drugs, including the widely-prescribed insulin-sensitizing drug metformin, are currently being investigated for AD therapy. However, their efficacy for tauopathy in vivo has not been tested.
  
  
  RESULTS
  Here, we report that in the P301S mutant human tau (P301S) transgenic mouse model of tauopathy, chronic administration of metformin exerts paradoxical effects on tau pathology. Despite reducing tau phosphorylation in the cortex and hippocampus via AMPK/mTOR and PP2A, metformin increases insoluble tau species (including tau oligomers) and the number of inclusions with β-sheet aggregates in the brain of P301S mice. In addition, metformin exacerbates hindlimb atrophy, increases P301S hyperactive behavior, induces tau cleavage by caspase 3 and disrupts synaptic structures.
  
  
  CONCLUSIONS
  These findings indicate that metformin pro-aggregation effects mitigate the potential benefits arising from its dephosphorylating action, possibly leading to an overall increase of the risk of tauopathy in elderly diabetic patients.
authors: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Via Morego 30, Genoa, Italy.
authors: Erica
authors: E
authors: Barini
authors: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Via Morego 30, Genoa, Italy.
authors: Odetta
authors: O
authors: Antico
authors: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, 361102, China.|Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
authors: Yingjun
authors: Y
authors: Zhao
authors: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Via Morego 30, Genoa, Italy.
authors: Francesco
authors: F
authors: Asta
authors: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Via Morego 30, Genoa, Italy.
authors: Valter
authors: V
authors: Tucci
authors: Nanochemistry Department, Electron Microscopy Lab, Istituto Italiano di Tecnologia, Via Morego 30, Genoa, Italy.
authors: Tiziano
authors: T
authors: Catelani
authors: Nanochemistry Department, Electron Microscopy Lab, Istituto Italiano di Tecnologia, Via Morego 30, Genoa, Italy.
authors: Roberto
authors: R
authors: Marotta
authors: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, 361102, China.|Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
authors: Huaxi
authors: H
authors: Xu
authors: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Via Morego 30, Genoa, Italy. laura.gasparini@iit.it.|Present Address: AbbVie Deutschland GmbH &Co. KG, Knollstr., 67061, Ludwigshafen, Germany. laura.gasparini@iit.it.
authors: Laura
authors: L
authors: Gasparini
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D024801:Tauopathies / Q000188:drug therapy* / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D008687:Metformin