Research Article| Volume 34, ISSUE 12, P824-838, December 15, 1993

Olfactory neuroblasts from Alzheimer donors: Studies on APP processing and cell regulation

      This paper is only available as a PDF. To read, Please Download here.


      Cell lines of continuously dividing human olfactory neuroblasts can be propagated using olfactory epithelium obtained from human donors at biopsy or autopsy. The expression of neuronal proteins in these cells, such as neurofilament protein and tau proetin, can be increased using a combination of factors including nerve growth factor, fibroblast growth factor, interleukin 1 and interleukin 6. These cells also express aspects of human disease. Olfactory neuroblasts generated from donors with the common, sporadic forms of Alzheimer's disease, show elevated levels of the direct precursor to β-amyloid, the amyloid precursor protein C-terminal derivative (CTD). When treated with the lysosomal inhibitor chloroquine, immunoblots of Alzheimer olfactory neuroblasts show seven-fold higher levels of CTDs than immunoblots from age-matched control neuroblasts. The disease related increases in CTDs can be reversed by treatment with agents that increase intracellular cyclic adenosine monophosphate (cAMP), such as dibutyril-cyclic-AMP, theophylline, and isoproteronol.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Caporaso G.L.
        • Gandy S.E.
        • Buxbaum J.D.
        • Ramabhadran T.V.
        • Greengard P.
        Protein phosphorylation regulates secretion of Alzheimer β/A4 amyloid precursor protein.
        in: Proc Natl Acad Sci USA. 89. 1992: 3055-3059
        • Cattaneo E.
        • McKay R.
        Proliferation and differentiation of neuronal stem cells regulated by nerve growth factor.
        Nature. 1990; 347: 762-765
        • Chamczynski P.
        • Sacchi N.
        Single step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.
        Anal Biochem. 1987; 162: 156-159
        • Chen J.
        • Cowan N.
        • Hirokawa N.
        Projection domains of MAP2 and tau determine spacings between microtubules in dendrites and axons.
        Nature. 1992; 360: 674-676
        • Citron M.
        • Oltersdorf T.
        • Haass C.
        • et al.
        Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production.
        Nature. 1992; 360: 672-674
        • Coon H.G.
        • Curcio F.
        • Sakaguchi K.
        • Brandi M.L.
        • Swerdlow R.D.
        Cell cultures of neuroblasts from rat olfactory epithelium that show odorant responses.
        in: Proc Natl Acad Sci USA. 86. 1989: 1703-1707
        • Davies P.
        The genetics of Alzheimer's disease: A review and a discussion of the implications.
        Neurobiol Aging. 1986; 7: 459-466
        • Esch F.
        • Keim P.S.
        • Beattie E.C.
        • et al.
        Cleavage of amyloid β peptide during constitutive processing of its precursor.
        Science. 1990; 248: 1122-1124
        • Escourolle R.
        • Poirer J.
        2nd ed. Manual of Basic Neuropathology. WB Saunders Co, Philadelphia1978: 3-4 (Translated by Rubinstein LG)
        • Glenner G.G.
        • Wong C.W.
        Initial report of the purification and characterization of a novel cerebrovascular amyloid protein.
        Biochem Biophys Res Commun. 1984; 120: 885-890
        • Goate A.
        • Chartier-Harlin M.C.
        • Mullan M.
        • et al.
        Segregation of a missence mutation in the amyloid precursor protein gene with familial Alzheimer's disease.
        Nature. 1991; 349: 704-706
        • Golde T.E.
        • Estus S.
        • Usiak M.
        • Younkin L.H.
        • Younkin S.G.
        Expression of a β amyloid protein precursor mRNAs: Recognition of a novel alternatively spliced form and quantitation in Alzheimer's disease using PCR.
        Neuron. 1990; 4: 253-267
        • Golde T.E.
        • Estus S.
        • Younkin L.H.
        • Selkoe D.J.
        • Younkin S.G.
        Processing of the amyloid protein precursor to potentially amyloidogenic derivatives.
        Science. 1992; 255: 728-730
        • Graves A.B.
        • van Duijn C.M.
        • Chandra V.
        • et al.
        • EURODEM Risk Factors Research Group
        Alcohol and tobacco consumption as risk factors for Alzheimer's disease: a collaborative re-analysis of case-control studies.
        Int J Epidemiol. 1991; 20: S48-S57
        • Graziadei P.P.C.
        Cell dynamics in the olfactory mucosa.
        Tissue Cell. 1973; 5: 113-131
        • Haass C.
        • Koo E.
        • Mellon A.
        • Hung A.
        • Selkoe D.
        Targeting of cell-surface β-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments.
        Nature. 1992; 357: 500-503
        • Haass C.
        • Schlossmacher M.
        • Hung A.
        • et al.
        Amyloid β-peptide is produced by cultured cells during normal metabolism.
        Nature. 1992; 359: 322-324
        • Hardy J.
        • Allsop D.
        Amyloid deposition as the central event in the aetiology of Alzheimer's disease.
        TIPS. 1991; 12: 383-388
        • Huang H.
        • Gibson G.
        Altered β-adrenergic receptor-stimulated cAMP formation in cultured skin fibroblasts from Alzheimer donors.
        J Biol Chem. 1993; 20: 14621-14646
        • Johnson G.
        • Brane D.
        • Lebovics R.
        • et al.
        Protein alterations in olfactory neuroblasts from Alzheimer donors.
        J Neurochem. 1993; (in press)
        • Johnson S.A.
        • McNeill T.
        • Cordell B.
        • Finch C.E.
        Relation of neuronal APP 751/APP-695 mRNA ratio and neuritic plaque density in Alzheimer's disease.
        Science. 1990; 248: 854-857
        • Johnson S.A.
        • Pasinetti G.M.
        • May P.C.
        • Ponte P.A.
        • Cordell B.
        • Finch C.
        Selective reduction of mRNA for the β-amyloid precursor protein that lacks a Kunitz-type protease inhibitor motif in cortex from Alzheimer brains.
        Exp Neurol. 1988; 102: 264-268
        • Kang J.
        • Lamaire H.G.
        • Unterbeck A.
        • et al.
        The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor.
        Nature. 1989; 325: 733-736
        • Kasahara T.
        • Yagisawa H.
        • Yamashita K.
        • Yamaguchi Y.
        • Akiyama Y.
        IL1 induces proliferation and IL6 mRNA expression in a human astrocytoma cell line: positive and negative modulation by cholera toxin and cAMP.
        Biochem Biophys Res Commun. 1990; 167: 1242-1248
        • Lee V.M.Y.
        • Balin B.J.
        • Otvos L.
        • Trojanowski J.Q.
        A68: A major subunit of paired helical filaments and derivatized forms of normal tau.
        Science. 1991; 251: 675-678
        • McDermott J.R.
        • Gibson A.M.
        The processing of Alzheimer A4/β-amyloid protein precursor: Identification of a human brain metallopeptidase which cleaves -Lys-Leu- in a model peptide.
        Biochem Biophys Res Commun. 1991; 179: 1148-1154
        • McKhann G.
        • Drachman D.
        • Folstein M.
        • Katzman R.
        • Price D.
        • Stadlan E.M.
        Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA work group.
        Neurology. 1984; 34: 939-944
        • Nakafuku M.
        • Satoh T.
        • Kaziro Y.
        Differentiation factors, including nerve growth factor, fibroblast growth factor, and interleukin-6, induce an accumulation of an active Tas.GAP complex in rat pheochromocytoma PC12 cells.
        J Biol Chem. 1992; 267: 19448-19454
        • Ohm T.
        • Bohl J.
        • Lemmer B.
        Reduced basal and stimulated (isoprenalin, Gpp(NH)p, forskolin) adenylate cyclase activity in Alzheimer's disease correlated with histopathological changes.
        Brain Res. 1991; 540: 229-236
        • Oltersdorf T.
        • Ward P.J.
        • Henriksson T.
        • et al.
        The Alzheimer amyloid precursor protein. Identification of a stable intermediate in the biosynthetic/degradative pathway.
        J Biol Chem. 1990; 265: 4492-4497
        • Palmert M.R.
        • Golde T.E.
        • Cohen M.L.
        • et al.
        Amyloid protein precursor messenger RNAs: Differential expression in Alzheimer's disease.
        Science. 1988; 241: 1080-1084
        • Sisodia S.S.
        • Koo E.H.
        • Beyreuther K.
        • Unterbeck A.
        • Price D.L.
        Evidence that β-amyloid protein in Alzheimer's disease is not derived by normal processing.
        Science. 1990; 248: 492-495
        • Talamo B.R.
        • Rudel R.
        • Kosik K.S.
        • et al.
        Pathological changes in olfactory neurons in patients with Alzheimer's disease.
        Nature. 1989; 337: 736-739
        • Tanzi R.
        • Vaula G.
        • Romano D.
        • et al.
        Assessment of amyloid β-protein precursor gene mutations in a large set of familial and sporadic Alzheimer disease cases.
        Am J Hum Genet. 1992; 51: 273-282
        • Van Nostrand W.
        • Farrow J.
        • Wagner S.
        • et al.
        The predominant form of the amyloid β-protein precursor in human brain is protease nexin 2.
        in: Proc Natl Acad Sci USA. 88. 1991: 10302-10306
        • Wasco W.
        • Bupp K.
        • Mangantanz M.
        • Gusella J.
        • Tanzi R.
        • Solomin F.
        Identification of a mouse brain cDNA that encodes a protein related to the Alzheimer's associated amyloid β-protein precursor.
        in: Proc Natl Acad Sci USA. 89. 1992: 10758-10762
        • Weidermann A.
        • Konig G.
        • Bunke D.
        • et al.
        Identification, biogenesis and localization of the precursors of Alzheimer's disease A4 amyloid protein.
        Cell. 1989; 571: 115-126
        • Wolozin B.L.
        • Davies P.
        Alzheimer-related neuronal protein A68: Specificity and distribution.
        Ann Neurol. 1987; 22: 521-526
        • Wolozin B.L.
        • Pruchnicki A.
        • Dickson D.W.
        • Davies P.
        A neuronal antigen in the brains of Alzheimer patients.
        Science. 1986; 232: 648-650
        • Wolozin B.
        • Zheng B.
        • Loren D.
        • et al.
        The β/A4 domain of APP: antigenic differences between cell lines.
        J Neurosci Red. 1992; 33: 189-195
        • Wolozin B.L.
        • Bacic M.
        • Merrill M.J.
        • et al.
        Differential expression of carboxyl terminal derivatives of amyloid precursor protein among cell lines.
        J Neurosci Res. 1992; 33: 163-169
        • Wolozin B.L.
        • Sunderland T.
        • Zheng B.B.
        • et al.
        Continuous culture of neuronal cells from adult human olfactory epithelium.
        J Mol Neurosci. 1992; 3: 137-146
        • Yankner B.A.
        • Duffy L.K.
        • Kirschner D.A.
        Neurotrophic and neurotoxic effects of amyloid β protein: Reversal by tachykinin neuropeptides.
        Science. 1990; 250: 279-282
        • Yoshikawa K.
        • Aizawa T.
        • Maruyama K.
        Neural differentiation increases expression of Alzheimer amyloid protein precursor gene in murine embryonal carcinoma cells.
        Biochem Biophys Res Commun. 1990; 171: 204-209