Differential processing of amyloid-beta precursor protein directs human embryonic stem cell proliferation and differentiation into neuronal precursor cells.
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.
Porayette
Prashob
P
Section of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin and Geriatric Research, Education and Clinical Center, Veterans Affairs Hospital, Madison, Wisconsin 53705, USA.
Gallego
Miguel J
MJ
Kaltcheva
Maria M
MM
Bowen
Richard L
RL
Vadakkadath Meethal
Sivan
S
Atwood
Craig S
CS
D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D011499:Protein Processing, Post-Translational
D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases