Article (Scientific journals)
Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology
Stygelbout, V.; Leroy, K.; Pouillon, V. et al.
2014In Brain: a Journal of Neurology, 137, p. 537-52
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Keywords :
Alzheimer pathology; inositol (1,3,4,5) tetrakisphosphate; Inositol (1,4,5) trisphosphate 3-kinase B
Abstract :
[en] S. Schurmans and J.-P. Brion contributed equally to this work Corresponding author: S. Schurmans, Laboratoire de Génétique Fonctionnelle, GIGA-Research Centre, Building 34, Université de Liège, rue de l’Hôpital 1, 4000-Liège, Belgium. Abstract: Inositol (1,4,5) trisphosphate 3-kinase B phosphorylates inositol 1,4,5-trisphosphate into inositol 1,3,4,5-tetrakisphosphate and controls signal transduction in various hematopoietic cells. Surprisingly, it has been reported that Inositol (1,4,5) trisphosphate 3-kinase B mRNA level is significantly increased in the cerebral cortex of Alzheimer patients, compared to control subjects. Since Extracellular signal-regulated kinases 1/2 activation is increased in Alzheimer brain and since Inositol (1,4,5) trisphosphate 3-kinase B is a regulator of Extracellular signal-regulated kinases 1/2 activation in some hematopoietic cells, we tested whether this increased activation in Alzheimer’s disease might be related to an increased activity of Inositol (1,4,5) trisphosphate 3-kinase B. We show here that Inositol (1,4,5) trisphosphate 3-kinase B protein level was 3 fold increased in the cerebral cortex of most Alzheimer patients, compared to control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Inositol (1,4,5) trisphosphate 3-kinase B overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to amyloid-β peptides overproduction. In this cellular model, an inhibitor of Mitogen-activated kinase kinases 1/2 completely prevented amyloid-β peptides overproduction. Transgenic overexpression of Inositol (1,4,5) trisphosphate 3-kinase B in mouse forebrain neurons was not sufficient to induce amyloid plaques formation or TAU hyperphosphorylation. However, in the 5X Familial Alzheimer’s Disease mouse model, neuronal Inositol (1,4,5) trisphosphate 3-kinase B overexpression significantly increased Extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer pathology as shown by increased astrogliosis, amyloid-β40 peptide production and TAU hyperphosphorylation. No impact on pathology was observed in the 5X Familial Alzheimer’s Disease mouse model when a catalytically inactive Inositol (1,4,5) trisphosphate 3-kinase B protein was overexpressed. Together, our results point to the Inositol (1,4,5) trisphosphate 3-kinase B /Inositol 1,3,4,5-tetrakisphosphate/Extracellular signal-regulated kinases 1/2 signaling pathway as an important regulator of neuronal cell apoptosis, Amyloid precursor protein processing and TAU phosphorylation in Alzheimer’s disease, and suggest that Inositol (1,4,5) trisphosphate 3-kinase B could represent a new target for reducing pathology in human AD patients with increased cortical Inositol (1,4,5) trisphosphate 3-kinase B expression.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Stygelbout, V.
Leroy, K.
Pouillon, V.
Ando, K.
D'Amico, E.
Jia, Y.
Luo, H. R.
Duyckaerts, C.
Erneux, C.
Schurmans, Stéphane   ;  Université de Liège - ULiège > Département de sciences fonctionnelles > Biochimie métabolique vétérinaire
Brion, J.-P. 
 These authors have contributed equally to this work.
Language :
English
Title :
Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology
Publication date :
2014
Journal title :
Brain: a Journal of Neurology
ISSN :
0006-8950
eISSN :
1460-2156
Publisher :
Oxford University Press, Oxford, United Kingdom
Volume :
137
Pages :
537-52
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 09 January 2014

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