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Activity requires soluble amyloid precursor protein α to promote neurite outgrowth in neural stem cell‐derived neurons via activation of the MAPK pathway
Author(s) -
GakharKoppole Nidhi,
Hundeshagen Phillip,
Mandl Claudia,
Weyer Sascha W.,
Allinquant Bernadette,
Müller Ulrike,
Ciccolini Francesca
Publication year - 2008
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2008.06398.x
Subject(s) - neurite , depolarization , mapk/erk pathway , microbiology and biotechnology , extracellular , amyloid precursor protein , phosphorylation , protein kinase a , neural stem cell , kinase , chemistry , biology , biochemistry , biophysics , stem cell , medicine , in vitro , disease , alzheimer's disease
It is known that activity modulates neuronal differentiation in the adult brain but the signalling mechanisms underlying this process remain to be identified. We show here that activity requires soluble amyloid precursor protein (sAPP) to enhance neurite outgrowth of young neurons differentiating from neural stem cells. Inhibition of sAPP secretion and anti‐APP antibodies both abolished the effect of depolarization on neurite outgrowth, whereas exogenous sAPPα, similar to depolarization, induced neurite elongation. Depolarization and sAPPα both required active N ‐methyl‐ d ‐aspartic acid receptor (NMDAR) and mitogen‐activated protein kinase (MAPK)/extracellular signal‐regulated kinase (ERK) recruitment to induce neurite outgrowth. However, depolarization and sAPPα played different roles in modulating this signalling cascade. Depolarization induced ERK phosphorylation with fast kinetics via activation of NMDAR. By contrast, acute application of sAPPα did not lead to ERK activation. However, continuous generation of sAPPα was necessary for depolarization‐induced ERK phosphorylation, indicating that sAPPα promotes MAPK/ERK recruitment by an indirect mechanism. In addition, we found that blockade of NMDAR down‐regulated APP expression, whereas depolarization increased sAPPα, suggesting that activity may also act upstream of sAPP signalling by regulating the amount of cellular APP and extracellular sAPPα. Finally, we show that soluble amyloid precursor‐like protein 2 (sAPLP2), but not sAPLP1, is functionally redundant to sAPP in promoting neurite outgrowth and that soluble members of the APP family require membrane‐bound APP to enhance neurite outgrowth. In summary, these experiments indicate a novel role of APP family members in activity‐dependent neuronal differentiation.