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 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. 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. The amyloid-β precursor protein (AβPP) 5The abbreviations used are: AβPPamyloid-β precursor proteinAβamyloid-βhESChuman embryonic stem cellNPCneural precursor cellADAlzheimer diseaseDSDown syndromesAβPPsoluble AβPPMEFmouse embryonic fibroblastDMEMDulbecco's modified Eagle's mediumDPBSDulbecco's phosphate-buffered salineGFAPglial fibrillary acidic proteinGAPDHglyceraldehyde-3-phosphate dehydrogenaseELISAenzyme-linked immunosorbent assayDMSOdimethyl sulfoxidefAβfibrillar AβEdUrd5-ethynyl-2′-deoxyuridinePBSphosphate-buffered salineEBembryoid bodyAPH-1anterior pharynx defective-1PEN-2presenilin enhancer-2ADDLAβ-derived diffusible ligandBACEβ-site AβPP-cleaving enzymeOCToctamer. is a ubiquitously expressed transmembrane protein whose cleavage product, the amyloid-β (Aβ) protein, is deposited in amyloid plaques in the aged brain, following head injury, and in the neurodegenerative conditions of Alzheimer disease (AD) and Down syndrome (DS). AβPP has structural similarity to growth factors (1.Rossjohn J. Cappai R. Feil S.C. Henry A. McKinstry W.J. Galatis D. Hesse L. Multhaup G. Beyreuther K. Masters C.L. Parker M.W. Nat. Struct. Biol. 1999; 6: 327-331Crossref PubMed Scopus (210) Google Scholar) and modulates several important neurotrophic functions, including neuritogenesis, synaptogenesis, and synaptic plasticity (2.Gralle M. Ferreira S.T. Prog. Neurobiol. 2007; 82: 11-32Crossref PubMed Scopus (138) Google Scholar). The function of AβPP during early embryogenesis and neurogenesis has not been well described. amyloid-β precursor protein amyloid-β human embryonic stem cell neural precursor cell Alzheimer disease Down syndrome soluble AβPP mouse embryonic fibroblast Dulbecco's modified Eagle's medium Dulbecco's phosphate-buffered saline glial fibrillary acidic protein glyceraldehyde-3-phosphate dehydrogenase enzyme-linked immunosorbent assay dimethyl sulfoxide fibrillar Aβ 5-ethynyl-2′-deoxyuridine phosphate-buffered saline embryoid body anterior pharynx defective-1 presenilin enhancer-2 Aβ-derived diffusible ligand β-site AβPP-cleaving enzyme octamer. AβPP is processed by at least two pathways, the non-amyloidogenic and amyloidogenic pathways. Non-amyloidogenic processing of AβPP yields secreted AβPPα (sAβPPα), the secreted extracellular domain of AβPP that acts as a growth factor for many cell types and promotes neuritogenesis (3.Milward E.A. Papadopoulos R. Fuller S.J. Moir R.D. Small D. Beyreuther K. Masters C.L. Neuron. 1992; 9: 129-137Abstract Full Text PDF PubMed Scopus (402) Google Scholar). Amyloidogenic processing of AβPP releases sAβPPβ, the AβPP intracellular domain, and Aβ proteins. The Aβ protein has both neurotoxic and neurotrophic properties (4.Yankner B.A. Duffy L.K. Kirschner D.A. Science. 1990; 250: 279-282Crossref PubMed Scopus (1917) Google Scholar) dependent on the differentiation state of the neuron; Aβ is neurotoxic to differentiating neurons via a mechanism involving differentiation-associated increases in the phosphorylation of the microtubule-associated protein tau (5.Liu T. Perry G. Chan H.W. Verdile G. Martins R.N. Smith M.A. Atwood C.S. J. Neurochem. 2004; 88: 554-563Crossref PubMed Scopus (83) Google Scholar) but neurotrophic to undifferentiated embryonic neurons. Evidence supporting a neurotrophic function for Aβ during development include its neurogenic activity toward rat neural stem cells (4.Yankner B.A. Duffy L.K. Kirschner D.A. Science. 1990; 250: 279-282Crossref PubMed Scopus (1917) Google Scholar, 5.Liu T. Perry G. Chan H.W. Verdile G. Martins R.N. Smith M.A. Atwood C.S. J. Neurochem. 2004; 88: 554-563Crossref PubMed Scopus (83) Google Scholar, 6.López-Toledano M.A. Shelanski M.L. J. Neurosci. 2004; 24: 5439-5444Crossref PubMed Scopus (209) Google Scholar). Consistent with these data, two studies have demonstrated increased hippocampal neurogenesis in young transgenic mice overexpressing human APPSw,Ind (7.Jin K. Galvan V. Xie L. Mao X.O. Gorostiza O.F. Bredesen D.E. Greenberg D.A. Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 13363-13367Crossref PubMed Scopus (401) Google Scholar, 8.López-Toledano M.A. Shelanski M.L. J. Alzheimers Dis. 2007; 12: 229-240Crossref PubMed Scopus (151) Google Scholar). Recently we reported that human embryonic stem cells (hESCs) express AβPP and that both the stemness of the cells and the pregnancy-associated hormone human chorionic gonadotropin alter AβPP expression (9.Porayette P. Gallego M.J. Kaltcheva M.M. Meethal S.V. Atwood C.S. Biochem. Biophys. Res. Commun. 2007; 364: 522-527Crossref PubMed Scopus (26) Google Scholar). These results suggest a functional role for AβPP during early human embryogenesis. To further investigate the function of AβPP and its cleavage products during early embryonic neurogenesis, we examined the expression and processing of this protein and its role in proliferation and differentiation of hESCs into neural precursor cells (NPCs). We found that amyloidogenic processing of AβPP promotes hESC proliferation whereas non-amyloidogenic processing induces hESC differentiation into NPCs. These data reveal an important function for AβPP during early human embryonic neurogenesis. Our data imply that any dysregulation in AβPP processing that leads to altered sAβPPα/Aβ production could result in aberrant neurogenesis as reported in the AD and DS brains. Pluripotent H9 hESCs (passage 22–32; XX karyotype; also known as WA09, a National Institutes of Health registered line) were obtained from WiCell Research Institute (Madison, were mouse embryonic fibroblast cells in with of to addition of cells were in Dulbecco's modified Eagle's medium with and of hESCs were on this and in the of medium with fibroblast growth factor and of cells required to with of a of of into and a hESCs also were on a from a in the of medium a medium by WiCell Research Institute V. J. Nat. PubMed Scopus Google Scholar). in was added to well of a and for at at hESCs were these cells were by a of in and the were into with and in The medium was in the the formation of the during human embryogenesis J. M. D. A. M. 6: PubMed Google Scholar). Pluripotent hESCs on in a were with of Dulbecco's phosphate-buffered saline were with of in at in the the into were with of a for The was in a for with the of the of the was for of the The of were and the was The were to in the for to the was with and the hESC were in and modified Dulbecco's medium in these and conditions in on an with for to the hESCs to into The and the the of these to the The for the differentiation of hESCs into in NPC development in of and S.C. Biol. Google Scholar). hESCs into that into neural that hESCs to a development of the in the when the neural forms in a human R. PubMed Scopus Google Scholar, S.C. J. Res. 12: PubMed Scopus Google Scholar). Pluripotent hESC on in were with and with of in and at in the of the to The was to the the into The hESC were in in a embryonic stem cell growth medium and for with of medium to embryonic stem cell were to the in a neural induction medium and fibroblast growth this in the of and into neural a of of differentiation The neural induction medium was The in the were differential in and for in neural induction medium to the cells to to the the cells of were to to of these were and for nestin to NPC The were by the a were and were as (9.Porayette P. Gallego M.J. Kaltcheva M.M. Meethal S.V. Atwood C.S. Biochem. Biophys. Res. Commun. 2007; 364: 522-527Crossref PubMed Scopus (26) Google Scholar). of the that in protein expression during the was to an to protein P. Gallego M.J. Kaltcheva M.M. Meethal S.V. Atwood C.S. Biochem. Biophys. Res. Commun. 2007; 364: 522-527Crossref PubMed Scopus (26) Google Scholar). this we to to protein as (5.Liu T. Perry G. Chan H.W. Verdile G. Martins R.N. Smith M.A. Atwood C.S. J. Neurochem. 2004; 88: 554-563Crossref PubMed Scopus (83) Google Scholar). The following were used this nestin amyloid-β precursor protein, amyloid-β precursor protein, anterior pharynx defective-1 and amyloid-β, and amyloid-β from of presenilin enhancer-2 glial fibrillary acidic protein presenilin glyceraldehyde-3-phosphate dehydrogenase and and hESC and NPC were for Aβ enzyme-linked immunosorbent assay hESCs and were with and with and The cell was at for to a and cell The was for Aβ by The cell was with and to proteins. The was in at for the was in to a of of has been not to M. PubMed Scopus Google was the The were to a and to the the was with that the of the Aβ known of Aβ and were added to the and at The was to and a was added that to the of Aβ and a to was The was was and Aβ was at on a The of Aβ was expressed as of were and by and by the M. 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Pluripotent hESCs were into embryoid into early in that of and cells 1999; PubMed Scopus Google Scholar). of and the in of a neural S.C. Biol. Google Scholar). To the of hESC we these cell for a factor that is required to stem cell and that is a of that J. Smith Nat. 24: PubMed Scopus Google Scholar). marker was in human cells and as for was in hESCs on in was in and was in with the of was an in the expression of the NPC marker nestin in and We this with a of for of including an of the of AβPP an the of Aβ an the of AβPP and an of Aβ both the and forms of AβPP that were expressed cell The a of AβPP cleavage products including and the Aβ of AβPP of with the including and and and and and AβPP of and The expression of both the and was increased with the differentiation of hESCs into and NPCs. the of AβPP also the a β-secretase cleavage of AβPP R. E.A. P. P. R. Fuller J. J. M.A. T. J. G. M. 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Full Text Full Text PDF PubMed Scopus Google normally express to of a of the expression of nestin of a role for in NPC formation. Together these results that non-amyloidogenic products of AβPP hESC differentiation toward NPCs. Aβ production from hESCs to Aβ in rat neurons is dependent differentiation-associated increases in tau and expression (5.Liu T. Perry G. Chan H.W. Verdile G. Martins R.N. Smith M.A. Atwood C.S. J. Neurochem. 2004; 88: 554-563Crossref PubMed Scopus (83) Google and undifferentiated hESCs not to Aβ we examined the differentiation of hESCs into also increases to Aβ by with for a in nestin and expression that Aβ was suppressed of cells in is we used protein as a marker of cell protein with To that was to we the expression of a marker of expression increased that to a of in the Our data suggest that the differential processing of AβPP regulates hESC proliferation and differentiation of hESCs into NPCs. The of the amyloidogenic pathway in hESCs was associated with cell proliferation as by the expression of β-secretase and but expression of in hESCs with and the production of Aβ by hESCs with the by Aβ on hESCs and the of hESC proliferation inhibition of Aβ production The of the non-amyloidogenic pathway was associated with hESC differentiation into as by an in functional expression in β-secretase increases in nestin expression and inhibition of hESC proliferation and increased nestin expression in The differential processing of AβPP in hESCs was by the expression of of AβPP and and and the functional of these AβPP cleavage products is in expression with differentiation a function during and functional reported include and AβPP cleavage products in human K. R.N. J. Sci. Full Text Full Text PDF PubMed Scopus Google Scholar, G. Small Multhaup G. Beyreuther K. Masters C.L. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar) and transgenic mice L. J. D. T. D. D. K. 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Full Text Full Text PDF PubMed Scopus Google stem cells in the DS of differentiating during neurogenesis to functional with such in AβPP processing also to the of AD in DS studies required to these data reveal that the early expression and differential processing of AβPP important for neurogenesis during early embryogenesis. in the processing of AβPP by cells neural stem cells in the during the cell and cell in AD and Our data hESCs as a for both neurogenesis and these results have important for at Aβ production as well as stem cell for neurodegenerative and head We the WiCell Research Institute for hESC and We to for with the with