title: Obesity, diabetes, and leptin resistance promote tau pathology in a mouse model of disease.
abstract: Obesity and type 2 diabetes mellitus (T2DM) convey an increased risk for developing dementia. The microtubule-associated protein tau is implicated in neurodegenerative disease by undergoing hyperphosphorylation and aggregation, leading to cytotoxicity and neurodegeneration. Enzymes involved in the regulation of tau phosphorylation, such as GSK3β, are tightly associated with pathways found to be dysregulated in T2DM. We have shown previously that leptin-resistant mice, which develop obesity and a diabetic phenotype, display elevated levels of tau phosphorylation. Here we show cells cultured with leptin, an adipokine shown to have neuroprotective effects, reduces tau phosphorylation. To explore how this mechanism works in vivo we transduced an existing diabetic mouse line (Lepr(db/db)) with a tau mutant (tau(P301L)) via adeno-associated virus (AAV). The resulting phenotype included a striking increase in tau phosphorylation and the number of neurofibrillary tangles (NFTs) found within the hippocampus. We conclude that leptin resistance-induced obesity and diabetes accelerates the development of tau pathology. This model of metabolic dysfunction and tauopathy provides a new system in which to explore the mechanisms underlying the ways in which leptin resistance and diabetes influence development of tau pathology, and may ultimately be related to the development of NFTs.
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, United States.
authors.forename: T L
authors.initials: TL
authors.lastname: Platt
authors.affiliation: Sanders Brown Center on Aging, University of Kentucky, United States.
authors.forename: T L
authors.initials: TL
authors.lastname: Beckett
authors.affiliation: Sanders Brown Center on Aging, University of Kentucky, United States.
authors.forename: K
authors.initials: K
authors.lastname: Kohler
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, United States; Sanders Brown Center on Aging, University of Kentucky, United States.
authors.forename: D M
authors.initials: DM
authors.lastname: Niedowicz
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, United States; Sanders Brown Center on Aging, University of Kentucky, United States. Electronic address: mpmurp3@email.uky.edu.
authors.forename: M P
authors.initials: MP
authors.lastname: Murphy
mesh_terms: D000818:Animals; D003071:Cognition / Q000502:physiology; D000229:Dependovirus / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D005822:Genetic Vectors; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology*; D009765:Obesity / Q000473:pathology / Q000503:physiopathology*; D010766:Phosphorylation; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020738:Leptin; C054369:MAPT protein, human; C558298:Mapt protein, mouse; D016875:tau Proteins
keywords: Alzheimer’s disease; diabetes; leptin; obesity; tau