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.
Institute for Genetics, University of Cologne, D-50931 Cologne, Germany.
Markus
M
Schubert
Dinesh
D
Gautam
David
D
Surjo
Kojihiko
K
Ueki
Stephanie
S
Baudler
Dominic
D
Schubert
Tatsuya
T
Kondo
Jens
J
Alber
Norbert
N
Galldiks
Eckehardt
E
Küstermann
Saskia
S
Arndt
Andreas H
AH
Jacobs
Wilhelm
W
Krone
C Ronald
CR
Kahn
Jens C
JC
Brüning
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