title: High-fat diet increases tau expression in the brain of T2DM and AD mice independently of peripheral metabolic status.
abstract: Alzheimer's disease and type 2 diabetes mellitus are risk factors for each other. To investigate the effects of both genetic and high-fat-induced diabetic phenotype on the expression and exon 10 splicing of tau, we used the Alzheimer's disease mouse model (APdE9) cross-bred with the type 2 diabetes mouse model over-expressing insulin-like growth factor 2 in the pancreas. High-fat diet, regardless of the genotype, significantly induced the expression of four repeat tau mRNA and protein in the temporal cortex of female mice. The mRNA levels of three repeat tau were also significantly increased by high-fat diet in the temporal cortex, although three repeat tau expression was considerably lower as compared to four repeat tau. Moreover, high-fat diet significantly increased the mRNA ratio of four repeat tau vs. three repeat tau in the temporal cortex of these mice. All of these effects were independent of the peripheral hyperglycemia, hyperinsulinemia and insulin resistance. Increased four repeat tau and three repeat tau levels significantly associated with impaired memory and reduced rearing in the female mice. High-fat diet did not affect neuroinflammation, Akt/GSK3β signaling pathway or the expression of tau exon 10 splicing enhancers in the temporal cortex. Our study suggests that the high-fat diet independently of type 2 diabetes or Alzheimer's disease background induces the expression and exon 10 inclusion of tau in the brain of female mice.
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Mari
authors.initials: M
authors.lastname: Takalo
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Annakaisa
authors.initials: A
authors.lastname: Haapasalo
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Henna
authors.initials: H
authors.lastname: Martiskainen
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Kaisa M A
authors.initials: KM
authors.lastname: Kurkinen
authors.affiliation: A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
authors.forename: Henna
authors.initials: H
authors.lastname: Koivisto
authors.affiliation: A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
authors.forename: Pasi
authors.initials: P
authors.lastname: Miettinen
authors.affiliation: A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
authors.forename: Vinoth K M
authors.initials: VK
authors.lastname: Khandelwal
authors.affiliation: A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
authors.forename: Susanna
authors.initials: S
authors.lastname: Kemppainen
authors.affiliation: Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Kaminska
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Petra
authors.initials: P
authors.lastname: Mäkinen
authors.affiliation: Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland; Institute of Clinical Medicine - Neurosurgery, University of Eastern Finland, Kuopio, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Leinonen
authors.affiliation: Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Department of Clinical Nutrition and Obesity Center, Kuopio University Hospital, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Pihlajamäki
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.affiliation: Institute of Clinical Medicine - Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.affiliation: A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Tanila
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland. Electronic address: mikko.hiltunen@uef.fi.
authors.forename: Mikko
authors.initials: M
authors.lastname: Hiltunen
mesh_terms: D017398:Alternative Splicing; D000544:Alzheimer Disease / Q000097:blood / Q000150:complications / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal; D003433:Crosses, Genetic; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects*; D005260:Female; D006943:Hyperglycemia / Q000517:prevention & control; D006946:Hyperinsulinism / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000627:therapeutic use; D007333:Insulin Resistance; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D020449:Repetitive Sequences, Amino Acid; D013702:Temporal Lobe / Q000378:metabolism*; D015854:Up-Regulation; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; C558298:Mapt protein, mouse; D016875:tau Proteins
keywords: Alternative splicing; Alzheimer’s disease; High-fat diet; Tau; Type 2 diabetes