Open AccessRole for neuronal insulin resistance in neurodegenerative diseases
Author(s) -
Markus Schubert,
Dinesh Gautam,
David Surjo,
Kunikazu Ueki,
Stephanie Baudler,
David Schubert,
Tatsuya Kondo,
Jens Alber,
Norbert Galldiks,
Ekkehard Küstermann,
Saskia S. Arndt,
Andréas H. Jacobs,
Wilhelm Krone,
C. Ronald Kahn,
Jens C. Brüning
Publication year - 2004
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0308724101
Subject(s) - insulin receptor , hyperphosphorylation , protein kinase b , insulin resistance , phosphorylation , gsk 3 , biology , insulin , cyclin dependent kinase 5 , neuron , kinase , signal transduction , endocrinology , medicine , tau protein , neuroscience , alzheimer's disease , microbiology and biotechnology , protein kinase a , disease , mitogen activated protein kinase kinase
Impairment of insulin signaling in the brain has been linked to neurodegenerative diseases. To test the hypothesis that neuronal insulin resistance contributes to defects in neuronal function, we have performed a detailed analysis of brain/neuron-specific insulin receptor knockout (NIRKO) mice. We find that NIRKO mice exhibit a complete loss of insulin-mediated activation of phosphatidylinositol 3-kinase and inhibition of neuronal apoptosis. In intact animals, this loss results in markedly reduced phosphorylation of Akt and GSK3 beta, leading to substantially increased phosphorylation of the microtubule-associated protein Tau, a hallmark of neurodegenerative diseases. Nevertheless, these animals exhibit no alteration in neuronal proliferation/survival, memory, or basal brain glucose metabolism. Thus, lack of insulin signaling in the brain may lead to changes in Akt and GSK3 beta activity and Tau hyperphosphorylation but must interact with other mechanisms for development of Alzheimer's disease.