title: γ-Secretase modulators reduce endogenous amyloid β42 levels in human neural progenitor cells without altering neuronal differentiation.
abstract: Soluble γ-secretase modulators (SGSMs) selectively decrease toxic amyloid β (Aβ) peptides (Aβ42). 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 Aβ42 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 Aβ42 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.
authors.affiliation: *Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA; and Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: D'Avanzo
authors.affiliation: *Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA; and Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Sliwinski
authors.affiliation: *Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA; and Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wagner
authors.affiliation: *Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA; and Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.affiliation: *Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA; and Department of Neurosciences, University of California, San Diego, La Jolla, California, USA dkim@helix.mgh.harvard.edu dora_kovacs@hms.harvard.edu.
authors.forename: Doo Yeon
authors.initials: DY
authors.lastname: Kim
authors.affiliation: *Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA; and Department of Neurosciences, University of California, San Diego, La Jolla, California, USA dkim@helix.mgh.harvard.edu dora_kovacs@hms.harvard.edu.
authors.forename: Dora M
authors.initials: DM
authors.lastname: Kovacs
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D000089622:Doublecortin Domain Proteins; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014404:Tubulin / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D010446:Peptide Fragments; C498585:TUBB3 protein, human; D014404:Tubulin; C092862:amyloid beta-protein (10-43); D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer’s disease; Notch; ReNcell VM; SGSM; presenilin