Obesity, diabetes, and leptin resistance promote tau pathology in a mouse model of disease

T. L. Platt, T. L. Beckett, K. Kohler, D. M. Niedowicz, M. P. Murphy

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

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 (Leprdb/db) with a tau mutant (tauP301L) 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.

Original languageEnglish
Pages (from-to)162-174
Number of pages13
JournalNeuroscience
Volume315
DOIs
StatePublished - Feb 19 2016

Bibliographical note

Funding Information:
We would like to thank Dr. Ronald Klein for the use of his AAV constructs, Dr. Peter Davies for his donation of the PHF1 antibody to the Sanders-Brown Neuropathology Core, Dr. Chad Dickey for his donation of the HEK tau P301L cell line, and Dr. Michael Mendenhall for assistance in AAV generation. This work was funded by the NIH ( NS058382 , NS083692 , AG045809 , GM103486 , DK020579 ), the Coins for Alzheimer’s Research Trust ( CART ), the American Heart Association ( 13IRG14330016 ) and the Alzheimer’s Association ( IIRG-10-172905 ). The authors declare no competing financial interests.

Publisher Copyright:
© 2015 IBRO.

Keywords

  • Alzheimer's disease
  • Diabetes
  • Leptin
  • Obesity
  • Tau

ASJC Scopus subject areas

  • Neuroscience (all)

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