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

• DOI: 10.1074/jbc.m109.026328
• Publication Date: 2009-06-20T02:13:54Z
• Authors: Prashob Porayette; Miguel J. Gallego; Maria M. Kaltcheva; Richard L. Bowen; Sivan Vadakkadath...; Craig S. Atwood
• Keywords: Neurons; 0301 basic medicine; Amyloid beta-Protein Precursor; 03 medical and health sciences; Humans; Cell Differentiation; Amyloid Precursor Protein Secretases; Protein Processing, Post-Translational; Cells, Cultured; Embryonic Stem Cells; Cell Proliferation

The amyloid-beta precursor protein (AbetaPP) is a ubiquitously expressed transmembrane protein whose cleavage product, the amyloid-beta (Abeta) 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 AbetaPP via secretase enzymes regulates the proliferation and differentiation of hESCs. hESCs endogenously produce amyloid-beta, which when added exogenously in soluble and fibrillar forms but not oligomeric forms markedly increased hESC proliferation. The inhibition of AbetaPP cleavage by beta-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 AbetaPPalpha, which suppressed hESC proliferation and promoted the formation of NPCs. Together these data suggest that differential processing of AbetaPP is normally required for embryonic neurogenesis.