Knock-in of Mutated hTAU Causes Insulin Resistance, Inflammation and Proteostasis Disturbance in a Mouse Model of Frontotemporal Dementia

Claire Hull, Ruta Dekeryte, David J. Koss, Barry Crouch, Heather Buchanan, Mirela Delibegovic, Bettina Platt (Corresponding Author)

Research output: Contribution to journalArticle

Abstract

Diabetes and obesity have been implicated as risk factors for dementia. However, metabolic mechanisms and associated signalling pathways have not been investigated in detail in frontotemporal dementia. We therefore here characterised physiological, behavioural and molecular phenotypes of 3- and 8-month-old male tau knock-in (PLB2TAU) vs wild-type (PLBWT) mice. Homecage analysis suggested intact habituation but a dramatic reduction in exploratory activity in PLB2TAU mice. Deficits in motor strength were also observed. At 3 months, PLB2TAU mice displayed normal glucose handling but developed hyperglycaemia at 8 months, suggesting a progressive diabetic phenotype. Brain, liver and muscle tissue analyses confirmed tissue-specific deregulation of metabolic and homeostatic pathways. In brain, increased levels of phosphorylated tau and inflammation were detected alongside reduced ER regulatory markers, overall suggesting a downregulation in essential cellular defence pathways. We suggest that subtle neuronal expression of mutated human tau is sufficient to disturb systems metabolism and protein handling. Whether respective dysfunctions in tauopathy patients are also a consequence of tau pathology remains to be confirmed, but could offer new avenues for therapeutic interventions.

Original languageEnglish
JournalMolecular Neurobiology
Early online date8 Aug 2019
DOIs
Publication statusE-pub ahead of print - 8 Aug 2019

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Frontotemporal Dementia
Insulin Resistance
Inflammation
Tauopathies
Phenotype
Brain
Metabolic Networks and Pathways
Hyperglycemia
Dementia
Down-Regulation
Obesity
Pathology
Glucose
Muscles
Liver
Proteins
Handling (Psychology)
Therapeutics

Keywords

  • transgenic
  • knock-in
  • diabetes
  • insulin
  • glucose
  • ER stress
  • UPR
  • proteinopathy

Cite this

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title = "Knock-in of Mutated hTAU Causes Insulin Resistance, Inflammation and Proteostasis Disturbance in a Mouse Model of Frontotemporal Dementia",
abstract = "Diabetes and obesity have been implicated as risk factors for dementia. However, metabolic mechanisms and associated signalling pathways have not been investigated in detail in frontotemporal dementia. We therefore here characterised physiological, behavioural and molecular phenotypes of 3- and 8-month-old male tau knock-in (PLB2TAU) vs wild-type (PLBWT) mice. Homecage analysis suggested intact habituation but a dramatic reduction in exploratory activity in PLB2TAU mice. Deficits in motor strength were also observed. At 3 months, PLB2TAU mice displayed normal glucose handling but developed hyperglycaemia at 8 months, suggesting a progressive diabetic phenotype. Brain, liver and muscle tissue analyses confirmed tissue-specific deregulation of metabolic and homeostatic pathways. In brain, increased levels of phosphorylated tau and inflammation were detected alongside reduced ER regulatory markers, overall suggesting a downregulation in essential cellular defence pathways. We suggest that subtle neuronal expression of mutated human tau is sufficient to disturb systems metabolism and protein handling. Whether respective dysfunctions in tauopathy patients are also a consequence of tau pathology remains to be confirmed, but could offer new avenues for therapeutic interventions.",
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AU - Hull, Claire

AU - Dekeryte, Ruta

AU - Koss, David J.

AU - Crouch, Barry

AU - Buchanan, Heather

AU - Delibegovic, Mirela

AU - Platt, Bettina

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