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Amyloid Precursor Protein in Neuroendocrine Cells SPIROS EFTHIMIOPOULOS*, DIDO Vassilacopoulout, JAMES A

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Amyloid Precursor Protein in Neuroendocrine Cells SPIROS EFTHIMIOPOULOS*, DIDO Vassilacopoulout, JAMES A Proc. Natl. Acad. Sci. USA Vol. 93, pp. 8046-8050, July 1996 Neurobiology Cholinergic agonists stimulate secretion of soluble full-length amyloid precursor protein in neuroendocrine cells SPIROS EFTHIMIOPOULOS*, DIDO VASSILACOPOULOUt, JAMES A. RIPELLINO*t, NIKOLAOS TEZAPSIDIS*, AND NIKoLAos K. ROBAKIS*§ *Department of Psychiatry and Fishberg Research Center for Neurobiology, Mount Sinai School of Medicine, New York, NY 10029; and tDepartment of Biochemistry, School of Physical and Mathematical Sciences, University of Athens, Athens, Greece Communicated by Herbert Weissbach, Roche Institute of Molecular Biology, Nutley, NJ, April 17, 1996 (received for review February 7, 1996) ABSTRACT The Af3 peptide of Alzheimer disease is de- by y-secretase at the C terminus of A13 (3, 4). However, in the rived from the proteolytic processing ofthe amyloid precursor transmembrane topology of APP, the peptide bond cleaved by proteins (APP), which are considered type I transmembrane ,y-secretase is located within the lipid bilayer and may not be glycoproteins. Recently, however, soluble forms of full-length easily accessible to proteases. It is therefore possible that A3 APP were also detected in several systems including chromaf- is derived from soluble nontransmembrane precursors where fin granules. In this report we used antisera specific for the the peptide bond cleaved by y-secretase is not protected by the cytoplasmic sequence of APP to show that primary bovine lipid bilayer (5, 6). chromaffin cells secrete a soluble APP, termed solAPPcyt, of Soluble truncated APPs (solAPPtrunc) are secreted as an apparent molecular mass of 130 kDa. This APP was proteolytic derivatives of APP that do not contain the cyto- oversecreted from Chinese hamster ovary cells transfected plasmic sequence. They have most or all of the extracytoplas- with a full-length APP cDNA indicating that solAPPcyt con- mic sequence and are produced after full-length APP is tained both the transmembrane and Aj8 sequence. Deglyco- cleaved by secretases (3, 7, 8). Recently, however, we showed sylation of solAPPcyt showed that it contained both N- and that the lumen of isolated bovine adrenal medullary chromaf- 0-linked sugars, suggesting that this APP was transported fin granules (CG), secretory vesicles used as a model for the through the endoplasmic reticulum-Golgi pathway. Secretion study of neuronal secretion (9), contained a soluble APP with of solAPPcyt from primary chromaffin cells was tempera- an intact cytoplasmic domain, and an apparent molecular mass ture-, time-, and energy-dependent and was stimulated by cell similar to that of full-length APP. This protein, termed here depolarization in a Ca2+-dependent manner. Cholinergic re- solAPPcyt, contained both the transmembrane and the A,B ceptor agonists, including acetylcholine, nicotine, or carba- sequence of APP (6). A similar APP was detected in the chol, stimulated the rapid secretion of solAPPcyt, a process culture media of pheochromocytoma PC12 cells and was that was inhibited by cholinergic antagonists. Stimulation of released from membrane preparations in vitro (5, 6). In solAPPcyt secretion was paralleled by a stimulation of secre- addition, soluble full-length APP species, as well as soluble tion in catecholamines and chromogranin A, indicating that truncated potentially amyloidogenic APP fragments with an secretion of solAPPcyt was mediated by chromaffin granule intact cytoplasmic domain, have been detected in several cell vesicles. Taken together, our results show that release of the culture systems (6, 10-12). It has been suggested that the latter potentially amyloidogenic solAPPcyt is an active cellular species are derived from solAPPcyt and may be further process mediated by both the constitutive and regulated degraded to produce AP3 (6). Although several functions, pathways. solAPPcyt was also detected in human cerebrospi- including cell growth (13), neurite outgrowth (14, 15), and nal fluid. Combined with the neuronal physiology of chro- stimulation of potassium channels (16), have been proposed maffin cells, our data suggest that cholinergic agonists may for solAPPtrunc, the function of the soluble full-length APP is stimulate the release of this APP in neuronal synapses where not known. The presence of this APP species in neuroendo- it may exert its biological function(s). Moreover, vesicular or crine secretory vesicles, however, suggested that it may be secreted solAPPcyt may serve as a soluble precursor of Aj3. secreted in response to neuronal stimulation. Here we report that primary chromaffin cell cultures secrete a glycosylated The A,B peptide, the main proteinaceous component of the solAPPcyt species of about 130 kDa. The secretion of this amyloid depositions of the Alzheimer disease (AD) brains, is potentially amyloidogenic APP was temperature-, time-, and derived from the proteolytic processing of the amyloid pre- energy-dependent and was regulated by cell depolarization cursor proteins (APPs) which display the structural character- and cholinergic agonists. istics of type I transmembrane glycoproteins. APPs contain a large extracytoplasmic region, a single transmembrane se- MATERIALS AND METHODS quence of about 24 residues, and a cytoplasmic (carboxyl- terminal) domain of 47 aa (for review, see ref. 1). Several APP Materials. Penicillin/streptomycin and L-glutamine were isoforms, resulting from alternative exon splicing, have been obtained from GIBCO/BRL. Collagenase was obtained from identified including APP751 which contains a 56-aa insert with Worthington, [35S]methionine/cysteine from Amersham, and high homology to the Kunitz-type serine protease inhibitors (2). The A,B sequence includes the last 28 aa of the extracy- Abbreviations: APP, amyloid precursor protein; AD, Alzheimer dis- ease; CHO, Chinese hamster ovary; FBS, fetal bovine serum; CG, toplasmic region and about 12 to 15 residues of the transmem- chromaffin granules; SRM, standard release medium; MTT, 3-[4,5- brane sequence of APP. It has been suggested that A,B is dimethylthiazole-2-yl]-2,5-diphenyl tetrazolium bromide; ER, endo- produced after membrane full-length APP is cleaved initially plasmic reticulum, CSF, cerebrospinal fluid; solAPPcyt, soluble cyto- by ,B-secretase at the N terminus of the A,B sequence, followed plasmic APP; solAPPtrunc; soluble truncated APP. by a cleavage of the resultant transmembrane APP fragment TPresent address: Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510. §To whom reprint requests should be addressed at: Department of The publication costs of this article were defrayed in part by page charge Psychiatry and Fishberg Research Center for Neurobiology, Mount payment. This article must therefore be hereby marked "advertisement" in Sinai School of Medicine, One Gustave Levy Place, Box 1229, New accordance with 18 U.S.C. §1734 solely to indicate this fact. York, NY 10029. 8046 Downloaded by guest on September 26, 2021 Neurobiology: Efthimiopoulos et aL Proc. Natl. Acad. Sci. USA 93 (1996) 8047 N-glycanase, O-glycanase, and neuraminidase from Genzyme. overnight with [35S]methionine/cysteine, and conditioned me- All other materials, including RPMI 1640 medium without dia from these cultures were prepared and centrifuged at high methionine and cysteine, McCoy's 5A culture medium, and speed as described (19). Supernatants were then immunopre- fetal bovine serum (FBS), were purchased from Sigma. Anti- cipitated using antisera Rl, CT15, or C8, each directed against cytoplasmic domain APP antisera Rl, CT15, and C8 directed the cytoplasmic domain of APP (6, 17, 18). As shown in Fig. against APP751 sequences 729-751, 732-751, and 737-751, LA, each of these antisera recognized a protein of =130 kDa respectively, were obtained as described (5, 17, 18). Anti- in the culture medium. This protein is not APLP2 (25) because chromogranin A antiserum was obtained from Incstar (Still- the latter is not recognized by the APP-specific antisera Rl and water, MN). CT15 (5, 6). A similar APP was detected in the conditioned Cell Cultures. Chinese hamster ovary (CHO) cells were medium of CHO cell cultures (Fig. 1B). The apparent molec- obtained from the American Type Culture Collection and ular mass of the solAPPcyt detected in the media of either were transfected with APP751 as described (19). Primary CHO or primary chromaffin cell cultures was intermediate cultures of bovine chromaffin cells were prepared from adre- between the molecular mass of the immature, endoplasmic nal medulla as described (20). Cells were plated onto poly-L- reticulum (ER), and mature forms of cellular full-length APP lysine-coated flat-bottom 24-well plates (Costar) at a density (26, 27). To exclude the possibility that solAPPcyt is derived of 5 x 105 cells per well in Dulbecco's modified Eagle's from an alternatively spliced mRNA, we transfected CHO cells medium (DMEM) supplemented with 2 mM L-glutamine, 0.01 with the full-length APP751 cDNA, which encodes both the mM sodium pyruvate, 10% heat-inactivated FBS, 10 ,uM A,B and transmembrane sequence (2). It can be seen in Fig. 1B cytocine arabinoside, 100 units of penicillin per ml, and 100 ,ug that the isolated transfected clones overexpressed secreted of streptomycin per ml. Three days after plating, chromaffin solAPPcyt, indicating that alternative splicing is not a prereq- cell cultures were metabolically labeled with 150 ,uCi of uisite for the production of solAPPcyt. Similar to the solAPP- [35S]methionine/cysteine per ml in DMEM (final
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