Regulation of the phosphatase calcineurin by insulin-like growth factor I unveils a key role of astrocytes in Alzheimer's pathology.
Mol Psychiatry
; 17(7): 705-18, 2012 Jul.
Article
in En
| MEDLINE
| ID: mdl-22005929
ABSTRACT
Whether insulin-like growth factor I (IGF-I) signaling in Alzheimer's disease (AD) is beneficial or detrimental remains controversial. We now show that a competitive regulation by IGF-I of the phosphatase calcineurin in reactive, but not in quiescent astrocytes drives Alzheimer's pathology. Calcineurin de-phosphorylates the transcription factor Foxo3 in response to tumor necrosis factor-α (TNFα), an inflammatory cytokine increased in AD, activating nuclear factor-κB (NFκB) inflammatory signaling in astrocytes. In turn, IGF-I inactivates and displaces Foxo3 from calcineurin in TNFα-stimulated astrocytes by recruiting the transcription factor peroxisome proliferator-activated receptor-γ, and NFκB signaling is inhibited. This antagonistic mechanism reversibly drives the course of the disease in AD mice, even at advanced stages. As hallmarks of this calcineurin/Foxo3/NFκB pathway are present in human AD brains, treatment with IGF-I may be beneficial by antagonizing it.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Insulin-Like Growth Factor I
/
Signal Transduction
/
Astrocytes
/
Plaque, Amyloid
/
Calcineurin
/
Alzheimer Disease
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Mol Psychiatry
Journal subject:
BIOLOGIA MOLECULAR
/
PSIQUIATRIA
Year:
2012
Document type:
Article
Affiliation country:
Spain