Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms.

Planel E, Tatebayashi Y, Miyasaka T, Liu L, Wang L, Herman M, Yu WH, Luchsinger JA, Wadzinski B, Duff KE, Takashima A
J Neurosci. 2007 27 (50): 13635-48

PMID: 18077675 · PMCID: PMC6673606 · DOI:10.1523/JNEUROSCI.3949-07.2007

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.

MeSH Terms (27)

Amyloid beta-Peptides Amyloid beta-Protein Precursor Animals Axons Body Temperature Diabetes Mellitus, Experimental Disease Models, Animal Dose-Response Relationship, Drug Enzyme Activation Epitopes Female Hippocampus Hypothermia Insulin Male Mice Mice, Inbred C57BL Microtubules Neocortex Neuropil Phosphorylation Protein Binding Protein Phosphatase 2 Solubility Streptozocin tau Proteins Time Factors

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