Inositol trisphosphate 3-kinase B is increased in human Alzheimer brain and exacerbates mouse Alzheimer pathology

[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

Additional URL :

http://reflexions.ulg.ac.be/AlzheimerITPKB

Available on ORBi :

since 09 January 2014

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