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

作者：Porayette Prashob; Gallego Miguel J; Kaltcheva Maria M; Bowen Richard L; Meethal Sivan Vadakkadath; Atwood Craig S^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284(35): 23806-23817.

DOI：10.1074/jbc.M109.026328

The amyloid-beta precursor protein (A beta PP) is a ubiquitously expressed transmembrane protein whose cleavage product, the amyloid-beta(A beta) 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 A beta PP 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 A beta PP 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 A beta PP alpha, which suppressed hESC proliferation and promoted the formation of NPCs. Together these data suggest that differential processing of A beta PP is normally required for embryonic neurogenesis.

• 出版日期2009-8-28