γ-Secretase modulators reduce endogenous amyloid ß42 levels in human neural progenitor cells without altering neuronal differentiation.
FASEB J
; 29(8): 3335-41, 2015 Aug.
Article
en En
| MEDLINE
| ID: mdl-25903103
ABSTRACT
Soluble γ-secretase modulators (SGSMs) selectively decrease toxic amyloid ß (Aß) peptides (Aß42). However, their effect on the physiologic functions of γ-secretase has not been tested in human model systems. γ-Secretase regulates fate determination of neural progenitor cells. Thus, we studied the impact of SGSMs on the neuronal differentiation of ReNcell VM (ReN) human neural progenitor cells (hNPCs). Quantitative PCR analysis showed that treatment of neurosphere-like ReN cell aggregate cultures with γ-secretase inhibitors (GSIs), but not SGSMs, induced a 2- to 4-fold increase in the expression of the neuronal markers Tuj1 and doublecortin. GSI treatment also induced neuronal marker protein expression, as shown by Western blot analysis. In the same conditions, SGSM treatment selectively reduced endogenous Aß42 levels by â¼80%. Mechanistically, we found that Notch target gene expressions were selectively inhibited by a GSI, not by SGSM treatment. We can assert, for the first time, that SGSMs do not affect the neuronal differentiation of hNPCs while selectively decreasing endogenous Aß42 levels in the same conditions. Our results suggest that our hNPC differentiation system can serve as a useful model to test the impact of GSIs and SGSMs on both endogenous Aß levels and γ-secretase physiologic functions including endogenous Notch signaling.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fragmentos de Péptidos
/
Diferenciación Celular
/
Péptidos beta-Amiloides
/
Secretasas de la Proteína Precursora del Amiloide
/
Células-Madre Neurales
/
Neuronas
Límite:
Humans
Idioma:
En
Revista:
FASEB J
Asunto de la revista:
BIOLOGIA
/
FISIOLOGIA
Año:
2015
Tipo del documento:
Article
País de afiliación:
Estados Unidos