Role for neuronal insulin resistance in neurodegenerative diseases.
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.
Schubert
Markus
M
Institute for Genetics, University of Cologne, D-50931 Cologne, Germany.
Gautam
Dinesh
D
Surjo
David
D
Ueki
Kojihiko
K
Baudler
Stephanie
S
Schubert
Dominic
D
Kondo
Tatsuya
T
Alber
Jens
J
Galldiks
Norbert
N
Küstermann
Eckehardt
E
Arndt
Saskia
S
Jacobs
Andreas H
AH
Krone
Wilhelm
W
Kahn
C Ronald
CR
Brüning
Jens C
JC
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D002531:Cerebellum / Q000503:physiopathology; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D018782:Maze Learning; D008568:Memory / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D019636:Neurodegenerative Diseases / Q000503:physiopathology*; D009474:Neurons / Q000502:physiology*; D011972:Receptor, Insulin / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D014055:Tomography, Emission-Computed
D011972:Receptor, Insulin; D005947:Glucose