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Blockade of the Interaction of Calcineurin with FOXO in Astrocytes Protects Against Amyloid-β-Induced Neuronal Death.
- Source :
-
Journal of Alzheimer's disease : JAD [J Alzheimers Dis] 2016 Apr 12; Vol. 52 (4), pp. 1471-8. - Publication Year :
- 2016
-
Abstract
- Astrocytes actively participate in neuro-inflammatory processes associated to Alzheimer's disease (AD), and other brain pathologies. We recently showed that an astrocyte-specific intracellular signaling pathway involving an interaction of the phosphatase calcineurin with the transcription factor FOXO3 is a major driver in AD-associated pathological inflammation, suggesting a potential new druggable target for this devastating disease. We have now developed decoy molecules to interfere with calcineurin/FOXO3 interactions, and tested them in astrocytes and neuronal co-cultures exposed to amyloid-β (Aβ) toxicity. We observed that interference of calcineurin/FOXO3 interactions exerts a protective action against Aβ-induced neuronal death and favors the production of a set of growth factors that we hypothesize form part of a cytoprotective pathway to resolve inflammation. Furthermore, interference of the Aβ-induced interaction of calcineurin with FOXO3 by decoy compounds significantly decreased amyloid-β protein precursor (AβPP) synthesis, reduced the AβPP amyloidogenic pathway, resulting in lower Aβ levels, and blocked the expression of pro-inflammatory cytokines TNFα and IL-6 in astrocytes. Collectively, these data indicate that interrupting pro-inflammatory calcineurin/FOXO3 interactions in astrocytes triggered by Aβ accumulation in brain may constitute an effective new therapeutic approach in AD. Future studies with intranasal delivery, or brain barrier permeable decoy compounds, are warranted.
- Subjects :
- Amyloid beta-Peptides metabolism
Animals
Astrocytes metabolism
Calcineurin metabolism
Calcineurin Inhibitors pharmacology
Forkhead Box Protein O3 metabolism
Interleukin-6 metabolism
Mice, Inbred C57BL
Tumor Necrosis Factor-alpha metabolism
Amyloid beta-Peptides antagonists & inhibitors
Astrocytes drug effects
Cell Death drug effects
Forkhead Box Protein O3 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1875-8908
- Volume :
- 52
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of Alzheimer's disease : JAD
- Publication Type :
- Academic Journal
- Accession number :
- 27079728
- Full Text :
- https://doi.org/10.3233/JAD-160149