Soluble form of amyloid precursor protein regulates proliferation of progenitors in the adult subventricular zone.
The amyloid precursor protein (APP) is a type I transmembrane protein of unknown physiological function. Its soluble secreted form (sAPP) shows similarities with growth factors and increases the in vitro proliferation of embryonic neural stem cells. As neurogenesis is an ongoing process in the adult mammalian brain, we have investigated a role for sAPP in adult neurogenesis. We show that the subventricular zone (SVZ) of the lateral ventricle, the largest neurogenic area of the adult brain, is a major sAPP binding site and that binding occurs on progenitor cells expressing the EGF receptor. These EGF-responsive cells can be cultured as neurospheres (NS). In vitro, EGF provokes soluble APP (sAPP) secretion by NS and anti-APP antibodies antagonize the EGF-induced NS proliferation. In vivo, sAPP infusions increase the number of EGF-responsive progenitors through their increased proliferation. Conversely, blocking sAPP secretion or downregulating APP synthesis decreases the proliferation of EGF-responsive cells, which leads to a reduction of the pool of progenitors. These results reveal a new function for sAPP as a regulator of SVZ progenitor proliferation in the adult central nervous system.
Caillé
Isabelle
I
CNRS UMR 8542, Ecole Normale Supérieure, 46 rue d'Ulm, 75005 Paris, France.
Allinquant
Bernadette
B
Dupont
Edmond
E
Bouillot
Colette
C
Langer
Andreas
A
Müller
Ulrike
U
Prochiantz
Alain
A
D000328:Adult; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D020547:Lateral Ventricles / Q000033:anatomy & histology / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D011485:Protein Binding; D013234:Stem Cells / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D007074:Immunoglobulin G; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor