Differential Processing of Amyloid-β Precursor Protein Directs Human Embryonic Stem Cell Proliferation and Differentiation into Neuronal Precursor Cells

The amyloid-β precursor protein (AβPP) is a ubiquitously expressed transmembrane protein whose cleavage product, the amyloid-β (Aβ) protein, is deposited in amyloid plaques in neurodegenerative conditions such as Alzheimer disease, Down syndrome, and head injury. We recently reported that this prote...

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Published in:The Journal of biological chemistry 2009-08, Vol.284 (35), p.23806-23817
Main Authors: Porayette, Prashob, Gallego, Miguel J., Kaltcheva, Maria M., Bowen, Richard L., Vadakkadath Meethal, Sivan, Atwood, Craig S.
Format: Article
Language:English
Subjects:
Amyloid beta-Protein Precursor - genetics
Amyloid beta-Protein Precursor - metabolism
Amyloid Precursor Protein Secretases - genetics
Amyloid Precursor Protein Secretases - metabolism
Cell Differentiation
Cell Proliferation
Cells, Cultured
Embryonic Stem Cells - cytology
Embryonic Stem Cells - metabolism
Humans
Molecular Basis of Cell and Developmental Biology
Neurons - cytology
Neurons - metabolism
Protein Processing, Post-Translational
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Summary:The amyloid-β precursor protein (AβPP) is a ubiquitously expressed transmembrane protein whose cleavage product, the amyloid-β (Aβ) protein, is deposited in amyloid plaques in neurodegenerative conditions such as Alzheimer disease, Down syndrome, and head injury. We recently reported that this protein, normally associated with neurodegenerative conditions, is expressed by human embryonic stem cells (hESCs). We now report that the differential processing of AβPP via secretase enzymes regulates the proliferation and differentiation of hESCs. hESCs endogenously produce amyloid-β, which when added exogenously in soluble and fibrillar forms but not oligomeric forms markedly increased hESC proliferation. The inhibition of AβPP cleavage by β-secretase inhibitors significantly suppressed hESC proliferation and promoted nestin expression, an early marker of neural precursor cell (NPC) formation. The induction of NPC differentiation via the non-amyloidogenic pathway was confirmed by the addition of secreted AβPPα, which suppressed hESC proliferation and promoted the formation of NPCs. Together these data suggest that differential processing of AβPP is normally required for embryonic neurogenesis.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M109.026328