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Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms

J Neurosci. 2007 Dec 12;27(50):13635-48. doi: 10.1523/JNEUROSCI.3949-07.2007.

Abstract

Hyperphosphorylated tau is the major component of paired helical filaments in neurofibrillary tangles found in Alzheimer's disease (AD) brains, and tau hyperphosphorylation is thought to be a critical event in the pathogenesis of the disease. The large majority of AD cases is late onset and sporadic in origin, with aging as the most important risk factor. Insulin resistance, impaired glucose tolerance, and diabetes mellitus (DM) are other common syndromes in the elderly also strongly age dependent, and there is evidence supporting a link between insulin dysfunction and AD. To investigate the possibility that insulin dysfunction might promote tau pathology, we induced insulin deficiency and caused DM in mice with streptozotocin (STZ). A mild hyperphosphorylation of tau could be detected 10, 20, and 30 d after STZ injection, and a massive hyperphosphorylation of tau was observed after 40 d. The robust hyperphosphorylation of tau was localized in the axons and neuropil, and prevented tau binding to microtubules. Neither mild nor massive tau phosphorylation induced tau aggregation. Body temperature of the STZ-treated mice did not differ from control animals during 30 d, but dropped significantly thereafter. No change in beta-amyloid (Abeta) precursor protein (APP), APP C-terminal fragments, or Abeta levels were observed in STZ-treated mice; however, cellular protein phosphatase 2A activity was significantly decreased. Together, these data indicate that insulin dysfunction induced abnormal tau hyperphosphorylation through two distinct mechanisms: one was consequent to hypothermia; the other was temperature-independent, inherent to insulin depletion, and probably caused by inhibition of phosphatase activity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Axons / metabolism
  • Body Temperature / drug effects
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / metabolism*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Epitopes / drug effects
  • Epitopes / metabolism
  • Female
  • Hippocampus / chemistry
  • Hippocampus / metabolism
  • Hypothermia / chemically induced
  • Hypothermia / metabolism
  • Insulin / metabolism*
  • Insulin / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microtubules / chemistry
  • Microtubules / metabolism
  • Neocortex / chemistry
  • Neocortex / metabolism
  • Neuropil / metabolism
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Protein Phosphatase 2 / antagonists & inhibitors
  • Protein Phosphatase 2 / metabolism
  • Solubility
  • Streptozocin / toxicity
  • Time Factors
  • tau Proteins / chemistry
  • tau Proteins / metabolism*

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Epitopes
  • Insulin
  • tau Proteins
  • Streptozocin
  • Protein Phosphatase 2