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γ‐Secretase modulators reduce endogenous amyloid β 42 levels in human neural progenitor cells without altering neuronal differentiation
Author(s) -
D'Avanzo Carla,
Sliwinski Christopher,
Wagner Steven L.,
Tanzi Rudolph E.,
Kim Doo Yeon,
Kovacs Dora M.
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.15-271015
Subject(s) - endogeny , progenitor cell , neurogenesis , neural stem cell , doublecortin , notch signaling pathway , microbiology and biotechnology , biology , chemistry , signal transduction , neuroscience , stem cell , central nervous system , biochemistry , dentate gyrus
Soluble γ‐secretase modulators (SGSMs) selectively decrease toxic amyloid β (Aβ) peptides (Aβ 42 ). 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 Aβ 42 levels by ~80%. 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 Aβ 42 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 Aβ levels and γ‐secretase physiologic functions including endogenous Notch signaling.—D'Avanzo, C., Sliwinski, C., Wagner, S. L., Tanzi, R. E., Kim, D. Y., Kovacs, D. M. γ‐Secretase modulators reduce endogenous amyloid β 42 levels in human neural progenitor cells without altering neuronal differentiation. FASEB J. 29, 3335‐3341 (2015). www.fasebj.org