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• W2077674018 abstract "Mutations in two related genes, PS1and PS2, account for the majority of early onset cases of familial Alzheimer's disease. PS1 and PS2 are homologous polytopic membrane proteins that are processed endoproteolytically into two fragments in vivo. In the present report we examine the fate of endogenous PS1 and PS2 after overexpression of human PS1 or PS2 in mouse N2a neuroblastoma cell lines and human PS1 in transgenic mice. Remarkably, in N2a cell lines and in brains of transgenic mice expressing human PS1, accumulation of human PS1 derivatives is accompanied by a compensatory, and highly selective, decrease in the steady-state levels of murine PS1 and PS2 derivatives. Similarly, the levels of murine PS1 derivatives are diminished in cultured cells overexpressing human PS2. To define the minimal sequence requirements for “replacement” we expressed familial Alzheimer's disease-linked and experimental deletion variants of PS1. These studies revealed that compromised accumulation of murine PS1 and PS2 derivatives resulting from overexpression of human PS1 occurs in a manner independent of endoproteolytic cleavage. Our results are consistent with a model in which the abundance of PS1 and PS2 fragments is regulated coordinately by competition for limiting cellular factor(s). Mutations in two related genes, PS1and PS2, account for the majority of early onset cases of familial Alzheimer's disease. PS1 and PS2 are homologous polytopic membrane proteins that are processed endoproteolytically into two fragments in vivo. In the present report we examine the fate of endogenous PS1 and PS2 after overexpression of human PS1 or PS2 in mouse N2a neuroblastoma cell lines and human PS1 in transgenic mice. Remarkably, in N2a cell lines and in brains of transgenic mice expressing human PS1, accumulation of human PS1 derivatives is accompanied by a compensatory, and highly selective, decrease in the steady-state levels of murine PS1 and PS2 derivatives. Similarly, the levels of murine PS1 derivatives are diminished in cultured cells overexpressing human PS2. To define the minimal sequence requirements for “replacement” we expressed familial Alzheimer's disease-linked and experimental deletion variants of PS1. These studies revealed that compromised accumulation of murine PS1 and PS2 derivatives resulting from overexpression of human PS1 occurs in a manner independent of endoproteolytic cleavage. Our results are consistent with a model in which the abundance of PS1 and PS2 fragments is regulated coordinately by competition for limiting cellular factor(s). Alzheimer's disease (AD) 1The abbreviations used are: AD, Alzheimer's disease; FAD, familial Alzheimer's disease; APP, amyloid precursor protein; PS, presenilin; NTF, NH2-terminal fragment; CTF, COOH-terminal fragment; ER, endoplasmic reticulum; CMV, cytomegalovirus; APLP, amyloid precursor-like protein; PAGE, polyacrylamide gel electrophoresis. 1The abbreviations used are: AD, Alzheimer's disease; FAD, familial Alzheimer's disease; APP, amyloid precursor protein; PS, presenilin; NTF, NH2-terminal fragment; CTF, COOH-terminal fragment; ER, endoplasmic reticulum; CMV, cytomegalovirus; APLP, amyloid precursor-like protein; PAGE, polyacrylamide gel electrophoresis. is a neurodegenerative disorder characterized by the presence of numerous senile plaques and neurofibrillary tangles in the cerebral cortex and hippocampus of affected individuals (1Wisniewski H.M. Terry R.D. Zimmerman H. Progress in Neuropathology. II. Grune and Stratton, New York1973: 1-26Google Scholar). Familial early onset AD (FAD) is associated with mutations in the amyloid precursor protein (APP) gene on chromosome 21 (for review, see Ref. 2Busfield F. Goate A.M. Gioate A.M. Ashall F. Pathology of Alzheimer's Disease. Academic Press, San Diego1995: 59-75Google Scholar), the PS1 gene on chromosome 14 (3Sherrington R. Froelich S. Sorbi S. Campion D. Chi H. Rogaeva E.A. Levesque G. Rogaev E.I. Lin C. Liang Y. Ikeda M. Mar L. Brice A. Agid Y. Percy M.E. Clerget-Darpoux F. Piacentini S. Marcon G. Nacmias B. Amaducci L. Frebourg T. Lannfelt L. Rommens J.M. St. George-Hyslop P.H. Hum. Mol. Genet. 1996; 5: 985-988Crossref PubMed Scopus (240) Google Scholar), and the PS2 gene on chromosome 1 (4Levy-Lahad E. Wasco W. Poorkaj P. Romano D.M. Oshima J. Pettingell W.H. Yu C.E. Jondro P.D. Schmidt S.D. Wang K. Crowley A.C. Fu Y.-H. Guenette S.Y. Galas D. Nemens E. Wijsman E.M. Bird T.D. Schellenberg G.D. Tanzi R.E. Science. 1995; 269: 973-977Crossref PubMed Scopus (2213) Google Scholar, 5Rogaev E.I. Sherrington R. Rogaeva E.A. Levesque G. Ikeda M. Liang Y. Chi H. Lin C. Holman K. Tsuda T. Mar L. Sorbi S. Nacmias B. Piacentini S. Amaducci L. Chumakov I. Cohen D. Lannfelt L. Fraser P.E. Rommens J.M. St. George-Hyslop P.H. Nature. 1995; 376: 775-778Crossref PubMed Scopus (1774) Google Scholar). Mutations in PS1 are causative in ∼25% of pedigrees with FAD. The mechanisms by which mutations in PS1/PS2predispose individuals to FAD have not been defined. However, levels of highly fibrillogenic Aβ42 species are elevated in fibroblast-conditioned medium and plasma from carriers ofPS1/PS2 mutations compared with unaffected family members (6Scheuner D. Eckman C. Jensen M. Song X. Citron M. Suzuki N. Bird T.D. Hardy J. Hutton M. Kukull W. Larson E. Levy-Lahad E. Viitanen M. Peskind E. Poorkaj P. Schellenberg G. Tanzi R. Wasco W. Lannfelt L. Selkoe D. Younkin S. Nat. Med. 1996; 2: 864-870Crossref PubMed Scopus (2249) Google Scholar). These studies have been confirmed by analysis of transfected cells and transgenic mice expressing FAD-linked PS1/PS2 variants (7Duff K. Eckman C. Zehr C. Yu X. Prada C.M. Perez-Tur J. Hutton M. Buee L. Harigaya Y. Yager D. Morgan D. Gordon M.N. Holcomb L. Refolo L. Zenk B. Hardy J. Younkin S. Nature. 1996; 383: 710-713Crossref PubMed Scopus (1309) Google Scholar, 8Borchelt D.R. Thinakaran G. Eckman C.B. Lee M.K. Davenport F. Ratovitski T. Prada C.M. Kim G. Seekins S. Yager D. Slunt H.H. Wang R. Seeger M. Levey A.I. Gandy S.E. Copeland N.G. Jenkins N.A. Price D.L. Younkin S.G. Sisodia S.S. Neuron. 1996; 17: 1005-1013Abstract Full Text Full Text PDF PubMed Scopus (1327) Google Scholar, 9Citron M. Westaway D. Xia W. Carlson G. Diehl T. Levesque G. Johnson-Wood K. Lee M. Seubert P. Davis A. Kholodenko D. Motter R. Sherrington R. Perry B. Yao H. Strome R. Lieberburg I. Rommens J. Kim S. Schenk D. Fraser P. St. George Hyslop P. Selkoe D.J. Nat. Med. 1997; 3: 67-72Crossref PubMed Scopus (1154) Google Scholar, 10Tomita T. Maruyama K. Saido T.C. Kume H. Shinozaki K. Tokuhiro S. Capell A. Walter J. Grunberg J. Haass C. Iwatsubo T. Obata K. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 2025-2030Crossref PubMed Scopus (347) Google Scholar). Collectively, these studies support the view that mutations in PS1 and PS2 cause AD by increasing the extracellular concentrations of highly fibrillogenic Aβ42 peptides.PS1 and PS2 are polytopic membrane proteins (11Doan A. Thinakaran G. Borchelt D.R. Slunt H.H. Ratovitski T. Podlisny M. Selkoe D.J. Seeger M. Gandy S.E. Price D.L. Sisodia S.S. Neuron. 1996; 17: 1023-1030Abstract Full Text Full Text PDF PubMed Scopus (355) Google Scholar) that share extensive amino acid sequence identity. In previous efforts, we documented that PS1 is subject to endoproteolytic cleavage and that the preponderant PS1-related species that accumulate in vivo are the ∼28-kDa NH2-terminal (NTF) and ∼17-kDa COOH-terminal (CTF) derivatives; the accumulation of NTF and CTF is highly regulated, saturable, and stoichiometric (12Thinakaran G. Borchelt D.R. Lee M.K. Slunt H.H. Spitzer L. Kim G. Ratovitski T. Davenport F. Nordstedt C. Seeger M. Hardy J. Levey A.I. Gandy S.E. Jenkins N.A. Copeland N.G. Price D.L. Sisodia S.S. Neuron. 1996; 17: 181-190Abstract Full Text Full Text PDF PubMed Scopus (937) Google Scholar). These studies have led to the suggestion that the endoproteolytically generated PS derivatives are the functional units in vivo. Recent studies indicate that PS2 is also endoproteolytically processed (10Tomita T. Maruyama K. Saido T.C. Kume H. Shinozaki K. Tokuhiro S. Capell A. Walter J. Grunberg J. Haass C. Iwatsubo T. Obata K. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 2025-2030Crossref PubMed Scopus (347) Google Scholar, 13Kim T.-W. Pettingell W.H. Hallmark O.G. Moir R.D. Wasco W. Tanzi R.E. J. Biol. Chem. 1997; 272: 11006-11010Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar). Although the biological significance of PS1/PS2 endoproteolysis is unclear, an FAD-linked variant that lacks sequences encoded by exon 9 (14Perez-Tur J. Froelich S. Prihar G. Crook R. Baker M. Duff K. Wragg M. Busfield F. Lendon C. Clark R.F. Roques P. Fuldner R.A. Johnston J. Cowburn R. Forsell C. Axelman K. Lilius L. Houlden H. Karran E. Roberts G.W. Rossor M. Adams M.d. Hardy J. Goate A. Lannfelt L. Hutton M. Neuroreport. 1995; 7: 297-301Crossref PubMed Scopus (237) Google Scholar) fails to be cleaved in vivo (12Thinakaran G. Borchelt D.R. Lee M.K. Slunt H.H. Spitzer L. Kim G. Ratovitski T. Davenport F. Nordstedt C. Seeger M. Hardy J. Levey A.I. Gandy S.E. Jenkins N.A. Copeland N.G. Price D.L. Sisodia S.S. Neuron. 1996; 17: 181-190Abstract Full Text Full Text PDF PubMed Scopus (937) Google Scholar).In this report we examine the fate of mouse PS1 and PS2 in mouse neuroblastoma cell lines that overexpress human PS1 or PS2. Remarkably, murine PS1 and PS2 derivatives fail to accumulate in these cells. These observations in cultured cells have been confirmed by the demonstration that murine PS2 is “replaced” by human PS1 derivatives in brains of transgenic mice expressing human PS1. Arguing against the view that replacement of murine PS1 and PS2 derivatives in cultured cells may be the result of artifacts associated with protein overexpression, we document that neither the steady-state levels of murinePS1/PS2 mRNA, synthetic rates of total membrane-bound or soluble protein, nor the steady-state levels of endoplasmic reticulum (ER) resident proteins, i.e. calnexin and BiP/GRP78, are altered in these cell lines. Interestingly, overexpression of the PS1ΔE9 variant in neuroblastoma cells also resulted in failed accumulation of murine PS1 derivatives, findings that suggest that endoproteolytic processing is not obligatory for replacement. In summary, our results are consistent with a model in which overexpressed human PS1 or PS2 competes with newly synthesized endogenous PS1/PS2 for limiting cellular component(s) that regulate endoproteolysis of full-length PS1/PS2 polypeptide and/or accumulation of the resulting derivatives.DISCUSSIONMutations in two related genes, PS1 and PS2, account for the majority of early onset cases of FAD (30Schellenberg G.D. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8552-8559Crossref PubMed Scopus (173) Google Scholar).PS1 and PS2 are multitransmembrane proteins that are expressed in brain and various peripheral tissues (3Sherrington R. Froelich S. Sorbi S. Campion D. Chi H. Rogaeva E.A. Levesque G. Rogaev E.I. Lin C. Liang Y. Ikeda M. Mar L. Brice A. Agid Y. Percy M.E. Clerget-Darpoux F. Piacentini S. Marcon G. Nacmias B. Amaducci L. Frebourg T. Lannfelt L. Rommens J.M. St. George-Hyslop P.H. Hum. Mol. Genet. 1996; 5: 985-988Crossref PubMed Scopus (240) Google Scholar, 5Rogaev E.I. Sherrington R. Rogaeva E.A. Levesque G. Ikeda M. Liang Y. Chi H. Lin C. Holman K. Tsuda T. Mar L. Sorbi S. Nacmias B. Piacentini S. Amaducci L. Chumakov I. Cohen D. Lannfelt L. Fraser P.E. Rommens J.M. St. George-Hyslop P.H. Nature. 1995; 376: 775-778Crossref PubMed Scopus (1774) Google Scholar, 12Thinakaran G. Borchelt D.R. Lee M.K. Slunt H.H. Spitzer L. Kim G. Ratovitski T. Davenport F. Nordstedt C. Seeger M. Hardy J. Levey A.I. Gandy S.E. Jenkins N.A. Copeland N.G. Price D.L. Sisodia S.S. Neuron. 1996; 17: 181-190Abstract Full Text Full Text PDF PubMed Scopus (937) Google Scholar, 28Lah J.J. Heilman C.J. Nash N.R. Rees H.D. Yi H. Counts S.E. Levey A.I. J. Neurosci. 1997; 17: 1971-1980Crossref PubMed Google Scholar,31Lee M.K. Slunt H.H. Martin L.J. Thinakaran G. Kim G. Gandy S.E. Seeger M. Koo E. Price D.L. Sisodia S.S. J. Neurosci. 1996; 16: 7513-7525Crossref PubMed Google Scholar). In preceding efforts, we and others documented that PS1 is subject to endoproteolytic processing in vivo (12Thinakaran G. Borchelt D.R. Lee M.K. Slunt H.H. Spitzer L. Kim G. Ratovitski T. Davenport F. Nordstedt C. Seeger M. Hardy J. Levey A.I. Gandy S.E. Jenkins N.A. Copeland N.G. Price D.L. Sisodia S.S. Neuron. 1996; 17: 181-190Abstract Full Text Full Text PDF PubMed Scopus (937) Google Scholar) and that the preponderant PS1-related polypeptides that accumulate in the brains of rodents, primates, and humans are NH2-terminal ∼28-kDa and COOH-terminal ∼17-kDa derivatives (7Duff K. Eckman C. Zehr C. Yu X. Prada C.M. Perez-Tur J. Hutton M. Buee L. Harigaya Y. Yager D. Morgan D. Gordon M.N. Holcomb L. Refolo L. Zenk B. Hardy J. Younkin S. Nature. 1996; 383: 710-713Crossref PubMed Scopus (1309) Google Scholar, 8Borchelt D.R. Thinakaran G. Eckman C.B. Lee M.K. Davenport F. Ratovitski T. Prada C.M. Kim G. Seekins S. Yager D. Slunt H.H. Wang R. Seeger M. Levey A.I. Gandy S.E. Copeland N.G. Jenkins N.A. Price D.L. Younkin S.G. Sisodia S.S. Neuron. 1996; 17: 1005-1013Abstract Full Text Full Text PDF PubMed Scopus (1327) Google Scholar, 9Citron M. Westaway D. Xia W. Carlson G. Diehl T. Levesque G. Johnson-Wood K. Lee M. Seubert P. Davis A. Kholodenko D. Motter R. Sherrington R. Perry B. Yao H. Strome R. Lieberburg I. Rommens J. Kim S. Schenk D. Fraser P. St. George Hyslop P. Selkoe D.J. Nat. Med. 1997; 3: 67-72Crossref PubMed Scopus (1154) Google Scholar, 12Thinakaran G. Borchelt D.R. Lee M.K. Slunt H.H. Spitzer L. Kim G. Ratovitski T. Davenport F. Nordstedt C. Seeger M. Hardy J. Levey A.I. Gandy S.E. Jenkins N.A. Copeland N.G. Price D.L. Sisodia S.S. Neuron. 1996; 17: 181-190Abstract Full Text Full Text PDF PubMed Scopus (937) Google Scholar, 28Lah J.J. Heilman C.J. Nash N.R. Rees H.D. Yi H. Counts S.E. Levey A.I. J. Neurosci. 1997; 17: 1971-1980Crossref PubMed Google Scholar, 31Lee M.K. Slunt H.H. Martin L.J. Thinakaran G. Kim G. Gandy S.E. Seeger M. Koo E. Price D.L. Sisodia S.S. J. Neurosci. 1996; 16: 7513-7525Crossref PubMed Google Scholar). We also documented that in transgenic mice overexpressing human PS1, the two derivatives accumulate to saturable levels and at 1:1 stoichiometry independent of the transgene-encoded mRNA (12Thinakaran G. Borchelt D.R. Lee M.K. Slunt H.H. Spitzer L. Kim G. Ratovitski T. Davenport F. Nordstedt C. Seeger M. Hardy J. Levey A.I. Gandy S.E. Jenkins N.A. Copeland N.G. Price D.L. Sisodia S.S. Neuron. 1996; 17: 181-190Abstract Full Text Full Text PDF PubMed Scopus (937) Google Scholar). The molecular mechanism(s) underlying this fascinating regulatory aspect of PS biology are yet to be established. Nevertheless, endoproteolysis appears to be a common catabolic step for all presenilins, including human and murine PS2 (10Tomita T. Maruyama K. Saido T.C. Kume H. Shinozaki K. Tokuhiro S. Capell A. Walter J. Grunberg J. Haass C. Iwatsubo T. Obata K. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 2025-2030Crossref PubMed Scopus (347) Google Scholar, 13Kim T.-W. Pettingell W.H. Hallmark O.G. Moir R.D. Wasco W. Tanzi R.E. J. Biol. Chem. 1997; 272: 11006-11010Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar) and a homologous protein inCaenorhabditis elegans, termed SEL-12 (32Li X. Greenwald I. Neuron. 1996; 17: 1015-1021Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar).To these latter observations, the present report provides an important insight. We document that in cultured cells overexpressing human PS1, saturable accumulation of human PS1 derivatives is accompanied by a compensatory decrease in accumulated murine PS1 and PS2 derivatives, this despite the persistence of murine PS1/PS2mRNA. Similarly, overexpression of human PS2 in cultured cells compromised accumulation of murine PS1-derived fragments. These effects are not unique to cultured cells since overexpression of human PS1 polypeptides in brains of transgenic mice leads to the reduced accumulation of murine PS1 (12Thinakaran G. Borchelt D.R. Lee M.K. Slunt H.H. Spitzer L. Kim G. Ratovitski T. Davenport F. Nordstedt C. Seeger M. Hardy J. Levey A.I. Gandy S.E. Jenkins N.A. Copeland N.G. Price D.L. Sisodia S.S. Neuron. 1996; 17: 181-190Abstract Full Text Full Text PDF PubMed Scopus (937) Google Scholar) and PS2 derivatives (this work). These observations are consistent with a model in which PS1 and PS2 molecules are stabilized and endoproteolytically processed by common, but limiting cellular factors, whereas excessively overexpressed PS polypeptides are rapidly degraded (Fig.8). In support of this view, recent studies have shown that in cultured cells, the vast majority of transiently overexpressed full-length PS polypeptides are rapidly turned over (t 1/2 ∼1 h), whereas the processed PS derivatives are long lived (t 1/2 ∼24 h) (13Kim T.-W. Pettingell W.H. Hallmark O.G. Moir R.D. Wasco W. Tanzi R.E. J. Biol. Chem. 1997; 272: 11006-11010Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar, 21Podlisny M.B. Citron M. Amarante P. Sherrington R. Xia W. Zhang J. Diehl T. Levesque G. Fraser P. Haass C. Koo E.H.M. Seubert P. St. George-Hyslop P. Teplow D.B. Selkoe D.J. Neurobiol. Dis. 1997; 3: 325-337Crossref PubMed Scopus (272) Google Scholar, 33Ratovitski T. Slunt H.H. Thinakaran G. Price D.L. Sisodia S.S. Borchelt D.R. J. Biol. Chem. 1997; 272: 24536-25541Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar).Although the mechanisms that underlie this interesting aspect of PS stabilization are presently uncertain, this phenomenon is not without biological precedent. For example, overexpression of chicken class IV (c-IV) β-tubulin isotype in Chinese hamster ovary cells resulted in limited accumulation of chicken c-IV β-tubulin polypeptides and was accompanied by a selective loss of endogenous CHO class IV (m-IV) β-tubulin isotype (34Sisodia S.S. Gay D.A. Cleveland D.W. New Biol. 1990; 2: 66-76PubMed Google Scholar). In this latter case, the authors argued that a limiting cellular pool of factors that bind selectively to either class IV β-tubulin- or class IV β-tubulin-enriched microtubules is responsible for stabilization of c-IV β-tubulin and replacement of m-IV β-tubulin isotype.With the concern that overexpression of membrane-bound or secretory proteins has a confounding affects on protein biogenesis in the ER and intracellular trafficking, we felt compelled to examine several aspects of ER metabolism in cells overexpressing PS1 and PS2 to confirm that the replacement of murine PS1/PS2 derivatives by human PS1 or PS2 is a highly specific and selective phenomenon. First, we documented that the biosynthesis of newly synthesized membrane-bound and soluble polypeptides in control cell lines and lines expressing human PS1 or PS2 was identical. Second, the steady-state levels of calnexin, an ER resident, integral membrane protein that facilitates folding and assembly of glycoproteins in the ER is identical in PS1, PS2, and control lines. Third, overexpression of PS1 or PS2 had no effect on the steady-state levels of BiP/GRP78, an ER lumenal chaperone that is normally induced by the accumulation of misfolded proteins in the ER. Fourth, induced overexpression of APP, a type I integral membrane glycoprotein, had no effect on the accumulation of murine PS1 derivatives. Finally, expression of COOH-terminally truncated human PS1 polypeptides had no effect on the levels of endogenous murine PS1 derivatives, indicating that murine PS1 gene expression is unaffected by the presence of high levels of truncated human PS1transcripts and polypeptides. Thus, we conclude that compromised accumulation of murine PS1 and PS2 derivatives resulting from overexpression of human PS1 or PS2 is a highly selective effect.In a variety of experimental settings it has become increasingly evident that the processed PS1/PS2 derivatives accumulate to saturable levels independent of the levels of full-length PS1/PS2 polypeptides (7Duff K. Eckman C. Zehr C. Yu X. Prada C.M. Perez-Tur J. Hutton M. Buee L. Harigaya Y. Yager D. Morgan D. Gordon M.N. Holcomb L. Refolo L. Zenk B. Hardy J. Younkin S. Nature. 1996; 383: 710-713Crossref PubMed Scopus (1309) Google Scholar, 8Borchelt D.R. Thinakaran G. Eckman C.B. Lee M.K. Davenport F. Ratovitski T. Prada C.M. Kim G. Seekins S. Yager D. Slunt H.H. Wang R. Seeger M. Levey A.I. Gandy S.E. Copeland N.G. Jenkins N.A. Price D.L. Younkin S.G. Sisodia S.S. Neuron. 1996; 17: 1005-1013Abstract Full Text Full Text PDF PubMed Scopus (1327) Google Scholar, 9Citron M. Westaway D. Xia W. Carlson G. Diehl T. Levesque G. Johnson-Wood K. Lee M. Seubert P. Davis A. Kholodenko D. Motter R. Sherrington R. Perry B. Yao H. Strome R. Lieberburg I. Rommens J. Kim S. Schenk D. Fraser P. St. George Hyslop P. Selkoe D.J. Nat. Med. 1997; 3: 67-72Crossref PubMed Scopus (1154) Google Scholar, 10Tomita T. Maruyama K. Saido T.C. Kume H. Shinozaki K. Tokuhiro S. Capell A. Walter J. Grunberg J. Haass C. Iwatsubo T. Obata K. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 2025-2030Crossref PubMed Scopus (347) Google Scholar, 12Thinakaran G. Borchelt D.R. Lee M.K. Slunt H.H. Spitzer L. Kim G. Ratovitski T. Davenport F. Nordstedt C. Seeger M. Hardy J. Levey A.I. Gandy S.E. Jenkins N.A. Copeland N.G. Price D.L. Sisodia S.S. Neuron. 1996; 17: 181-190Abstract Full Text Full Text PDF PubMed Scopus (937) Google Scholar, 13Kim T.-W. Pettingell W.H. Hallmark O.G. Moir R.D. Wasco W. Tanzi R.E. J. Biol. Chem. 1997; 272: 11006-11010Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar). Moreover, in several lines of transgenic mice, processed human PS1 derivatives accumulate to saturable levels independent of the levels of PS1 mRNA (12Thinakaran G. Borchelt D.R. Lee M.K. Slunt H.H. Spitzer L. Kim G. Ratovitski T. Davenport F. Nordstedt C. Seeger M. Hardy J. Levey A.I. Gandy S.E. Jenkins N.A. Copeland N.G. Price D.L. Sisodia S.S. Neuron. 1996; 17: 181-190Abstract Full Text Full Text PDF PubMed Scopus (937) Google Scholar). These observations have suggested that the cellular factor(s) involved in endoproteolysis or stabilization of PS1 derivatives may be limiting. Although little information is available regarding the molecular identity of the enzyme(s) responsible for PS1/PS2 endoproteolysis and factors responsible for fragment stability, we consider it unlikely that the regulated accumulation of PS fragments is dependent on competition for protease(s) responsible for cleavage. In support of this view, we demonstrate that expression of COOH-terminally truncated human PS1 polypeptides (PS1361Δ and PS1403Δ), which contain the proteolytic cleavage site but fail to be cleaved, do not influence accumulation of endogenous murine PS1 fragments. On the other hand, expression of noncleavable FAD-linked PS1ΔE9 variant results in the replacement of murine PS1 derivatives in cultured cells (this work) and in transgenic mice (29Lee M.K. Borchelt D.R. Kim G. Thinakaran G. Slunt H.H. Ratovitski T. Martin L.J. Kittur A. Gandy S. Levey A.I. Jenkins N. Copeland N. Price D.L. Sisodia S.S. Nat. Med. 1997; 3: 756-760Crossref PubMed Scopus (130) Google Scholar). Interestingly, we and others have demonstrated that although the PS1ΔE9 variant efficiently rescues an egg-laying defect in C. elegans lacking SEL-12 (35Levitan D. Doyle T.G. Brousseau D. Lee M.K. Thinakaran G. Slunt H.H. Sisodia S.S. Greenwald I. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 14940-14944Crossref PubMed Scopus (342) Google Scholar, 36Baumeister R. Leimer U. Zweekbronner I. Jakubek C. Grunberg J. Haass C. Genes Funct. 1997; 1: 149-159Crossref PubMed Scopus (185) Google Scholar) the human PS1 lacking the loop and COOH-terminal domains fails to do so (36Baumeister R. Leimer U. Zweekbronner I. Jakubek C. Grunberg J. Haass C. Genes Funct. 1997; 1: 149-159Crossref PubMed Scopus (185) Google Scholar). Thus, it is highly likely that the functional rescue by the PS1ΔE9 variant is a reflection of its stabilization by successful interaction with limiting cellular factor(s) or targeting to cellular compartments that are normally occupied by endoproteolytic derivatives of PS (33Ratovitski T. Slunt H.H. Thinakaran G. Price D.L. Sisodia S.S. Borchelt D.R. J. Biol. Chem. 1997; 272: 24536-25541Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar).The nature of subcellular compartments in which PS fragments accumulate has not been established. However, a major endoproteolytic site between amino acids 298 and 299 has been reported (21Podlisny M.B. Citron M. Amarante P. Sherrington R. Xia W. Zhang J. Diehl T. Levesque G. Fraser P. Haass C. Koo E.H.M. Seubert P. St. George-Hyslop P. Teplow D.B. Selkoe D.J. Neurobiol. Dis. 1997; 3: 325-337Crossref PubMed Scopus (272) Google Scholar). With this information, it will be important to generate end-specific antibodies to the NH2 terminus of the CTF or the extreme COOH terminus of the NTF to discriminate full-length PS1 from its cleaved derivatives. These reagents will be enormously useful for biochemical, cell biological, and morphological studies of PS1 metabolism and trafficking. Moreover, characterization of the protein(s) involved in targeting PS to the cleavage pathway and identification of the enzyme(s) responsible for the endoproteolysis of PS will facilitate future efforts aimed at clarifying the limiting step(s) that regulate the accumulated levels of processed PS1/PS2 derivatives. Alzheimer's disease (AD) 1The abbreviations used are: AD, Alzheimer's disease; FAD, familial Alzheimer's disease; APP, amyloid precursor protein; PS, presenilin; NTF, NH2-terminal fragment; CTF, COOH-terminal fragment; ER, endoplasmic reticulum; CMV, cytomegalovirus; APLP, amyloid precursor-like protein; PAGE, polyacrylamide gel electrophoresis. 1The abbreviations used are: AD, Alzheimer's disease; FAD, familial Alzheimer's disease; APP, amyloid precursor protein; PS, presenilin; NTF, NH2-terminal fragment; CTF, COOH-terminal fragment; ER, endoplasmic reticulum; CMV, cytomegalovirus; APLP, amyloid precursor-like protein; PAGE, polyacrylamide gel electrophoresis. is a neurodegenerative disorder characterized by the presence of numerous senile plaques and neurofibrillary tangles in the cerebral cortex and hippocampus of affected individuals (1Wisniewski H.M. Terry R.D. Zimmerman H. Progress in Neuropathology. II. Grune and Stratton, New York1973: 1-26Google Scholar). Familial early onset AD (FAD) is associated with mutations in the amyloid precursor protein (APP) gene on chromosome 21 (for review, see Ref. 2Busfield F. Goate A.M. Gioate A.M. Ashall F. Pathology of Alzheimer's Disease. Academic Press, San Diego1995: 59-75Google Scholar), the PS1 gene on chromosome 14 (3Sherrington R. Froelich S. Sorbi S. Campion D. Chi H. Rogaeva E.A. Levesque G. Rogaev E.I. Lin C. Liang Y. Ikeda M. Mar L. Brice A. Agid Y. Percy M.E. Clerget-Darpoux F. Piacentini S. Marcon G. Nacmias B. Amaducci L. Frebourg T. Lannfelt L. Rommens J.M. St. George-Hyslop P.H. Hum. Mol. Genet. 1996; 5: 985-988Crossref PubMed Scopus (240) Google Scholar), and the PS2 gene on chromosome 1 (4Levy-Lahad E. Wasco W. Poorkaj P. Romano D.M. Oshima J. Pettingell W.H. Yu C.E. Jondro P.D. Schmidt S.D. Wang K. Crowley A.C. Fu Y.-H. Guenette S.Y. Galas D. Nemens E. Wijsman E.M. Bird T.D. Schellenberg G.D. Tanzi R.E. Science. 1995; 269: 973-977Crossref PubMed Scopus (2213) Google Scholar, 5Rogaev E.I. Sherrington R. Rogaeva E.A. Levesque G. Ikeda M. Liang Y. Chi H. Lin C. Holman K. Tsuda T. Mar L. Sorbi S. Nacmias B. Piacentini S. Amaducci L. Chumakov I. Cohen D. Lannfelt L. Fraser P.E. Rommens J.M. St. George-Hyslop P.H. Nature. 1995; 376: 775-778Crossref PubMed Scopus (1774) Google Scholar). Mutations in PS1 are causative in ∼25% of pedigrees with FAD. The mechanisms by which mutations in PS1/PS2predispose individuals to FAD have not been defined. However, levels of highly fibrillogenic Aβ42 species are elevated in fibroblast-conditioned medium and plasma from carriers ofPS1/PS2 mutations compared with unaffected family members (6Scheuner D. Eckman C. Jensen M. Song X. Citron M. Suzuki N. Bird T.D. Hardy J. Hutton M. Kukull W. Larson E. Levy-Lahad E. Viitanen M. Peskind E. Poorkaj P. Schellenberg G. Tanzi R. Wasco W. Lannfelt L. Selkoe D. Younkin S. Nat. Med. 1996; 2: 864-870Crossref PubMed Scopus (2249) Google Scholar). These studies have been confirmed by analysis of transfected cells and transgenic mice expressing FAD-linked PS1/PS2 variants (7Duff K. Eckman C. Zehr C. Yu X. Prada C.M. Perez-Tur J. Hutton M. Buee L. Harigaya Y. Yager D. Morgan D. Gordon M.N. Holcomb L. Refolo L. Zenk B. Hardy J. Younkin S. Nature. 1996; 383: 710-713Crossref PubMed Scopus (1309) Google Scholar, 8Borchelt D.R. Thinakaran G. Eckman C.B. Lee M.K. Davenport F. Ratovitski T. Prada C.M. Kim G. Seekins S. Yager D. Slunt H.H. Wang R. Seeger M. Levey A.I. Gandy S.E. Copeland N.G. Jenkins N.A. Price D.L. Younkin S.G. Sisodia S.S. Neuron. 1996; 17: 1005-1013Abstract Full Text Full Text PDF PubMed Scopus (1327) Google Scholar, 9Citron M. Westaway D. Xia W. Carlson G. Diehl T. Levesque G. Johnson-Wood K. Lee M. Seubert P. Davis A. Kholodenko D. Motter R. Sherrington R. Perry B. Yao H. Strome R. Lieberburg I. Rommens J. Kim S. Schenk D. Fraser P. 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