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MOLECULAR CELL BIOLOGY OF ALZHEIMER AMYLOIDOGENESIS
20 September 1992 - 31 July 1995
NATIONAL INSTITUTE ON AGING
Total Funding: $ 544,235
Alzheimer's disease is characterized by clinical dementia in association with pathologic alterations in brain proteins. Structural lesions include extracellular beta/A4-amyloid deposits. Beta/A4-amyloid is derived through proteolysis of a large, transmembrane precursor, the beta/A4-amyloid precursor protein (APP). Mutations in the coding sequence of APP are associated with familial cerebral amyloidoses, pointing to the importance of APP in the pathogenesis of amyloidosis. The association of different APP-mutation genotypes with the cerebral amyloidosis phenotype strongly suggests that alternative amyloidogenic proteolysis may be a final common pathway in both familial and sporadic cerebral amyloidotic diseases, including Alzheimer's disease. A standard pathway for proteolysis of about 30% of APP molecules (in PC-12 cells) cleaves within the beta/A44- amyloid domain, precluding amyloid formation. The generation of beta/A4-amyloid must therefore occur via an alternative proteolytic pathway. Evidence for the existence of alternative pathways has emerged from several laboratories, in studies of human cerebral vessels, brain, and cells in continuous culture. Cell culture systems which generate microheterogeneous proteolysis of APP include the rat PC-12 line (under conditions of supraphysiological protein phosphorylation), the monkey fibroblast (following overexpression of human APP in recombinant vaccinia virus), the human APP-transfected human 293 cell, and the recombinant human APP-baculovirus infected Sf9 cell. The Sf9 system is particularly attractive because of the extraordinarily high-level expression of recombinant protein, providing convenience for purification and sequencing of species of interest. Sf9 cells faithfully recapitulate many of the biological properties of mammalian cells. When human APP is expressed in Sf9 cells, a portion of APP molecules is cleaved in a position exactly identical to the major cleavage site for proteolyzing APP in human cells, thus providing validity to the use of the Sf9 cell as a model system for APP proteolysis. At high multiplicities-of-infection, in addition to the cleavage of APP at this major conserved site (which generates a 14-15 Kda carboxyl-terminal fragment), Sf9 cells produce a discrete and limited number of other APP carboxyl-terminal fragments, including species of 16-, 17- and 25-Kda. By antigenic analysis, the 17-Kda species has been demonstrated to incorporate amino-terminal epitopes of the beta/A4-amyloid domain and is thus a putative amyloidogenic fragment. While there is mounting immunochemical evidence for such putative amyloidogenic fragments, direct protein sequencing of such a species has not been achieved, and is the primary goal of this proposal, using the baculoviral/Sf9 expression system. In addition, putative amyloidogenic mutant APP molecules (from familial cerebral amyloidoses) will be overexpressed in baculoviruses, and their proteolytic fragments characterized, purified and sequenced. The definitive identification of amyloidogenic pathways for APP proteolysis is crucial to the successful dissection of amyloidogenesis and to the design of strategies for in vitro models of amyloidogenesis.
42 Resulting Publications
L Lévesque; W Annaert; K Craessaerts; P M Mathews; M Seeger; R A Nixon; F Van Leuven; S Gandy; D Westaway; P St George-Hyslop; et al.Molecular medicine (Cambridge, Mass.) 1999;5(8):542-54.
H Komano; M Seeger; S Gandy; G T Wang; G A Krafft; R S Fuller
Involvement of cell surface glycosyl-phosphatidylinositol-linked aspartyl proteases in alpha-secretase-type cleavage and ectodomain solubilization of human Alzheimer beta-amyloid precursor protein in yeast.The Journal of biological chemistry 1998;273(48):31648-51.
G K Gouras; H Xu; J N Jovanovic; J D Buxbaum; R Wang; P Greengard; N R Relkin; S GandyJournal of neurochemistry 1998;71(5):1920-5.
N Y Calingasan; L C Park; L L Calo; R R Trifiletti; S E Gandy; G E GibsonThe American journal of pathology 1998;153(2):599-610.
K Taddei; D Yang; C Fisher; R Clarnette; J Hallmayer; R Barnetson; R Maller; W S Brooks; S Whyte; G A Nicholson; et al.Neuroscience letters 1998;246(3):178-80.
H Xu; G K Gouras; J P Greenfield; B Vincent; J Naslund; L Mazzarelli; G Fried; J N Jovanovic; M Seeger; N R Relkin; et al.Nature medicine 1998;4(4):447-51.
L C Walker; C A Parker; W J Lipinski; M J Callahan; R T Carroll; S E Gandy; J D Smith; M Jucker; C L BisgaierThe American journal of pathology 1997;151(5):1371-7.
N Y Calingasan; S E Gandy; G E GibsonNeuroreport 1997;8(11):2631-4.
M Seeger; C Nordstedt; S Petanceska; D M Kovacs; G K Gouras; S Hahne; P Fraser; L Levesque; A J Czernik; P S George-Hyslop; et al.Proceedings of the National Academy of Sciences of the United States of America 1997;94(10):5090-4.
H Xu; D Sweeney; R Wang; G Thinakaran; A C Lo; S S Sisodia; P Greengard; S GandyProceedings of the National Academy of Sciences of the United States of America 1997;94(8):3748-52.
T Suzuki; K Ando; T Isohara; M Oishi; G S Lim; Y Satoh; W Wasco; R E Tanzi; A C Nairn; P Greengard; et al.Biochemistry 1997;36(15):4643-9.
J B Kwok; K Taddei; M Hallupp; C Fisher; W S Brooks; G A Broe; J Hardy; M J Fulham; G A Nicholson; R Stell; et al.Neuroreport 1997;8(6):1537-42.
G K Gouras; N R Relkin; D Sweeney; D G Munoz; I R Mackenzie; S GandyAnnals of neurology 1997;41(3):402-4.
K Taddei; R Clarnette; S E Gandy; R N MartinsNeuroscience letters 1997;223(1):29-32.
D S Yang; J D Smith; Z Zhou; S E Gandy; R N MartinsJournal of neurochemistry 1997;68(2):721-5.
M Oishi; A C Nairn; A J Czernik; G S Lim; T Isohara; S E Gandy; P Greengard; T SuzukiMolecular medicine (Cambridge, Mass.) 1997;3(2):111-23.
L O Tjernberg; J Näslund; J Thyberg; S E Gandy; L Terenius; C NordstedtThe Journal of biological chemistry 1997;272(3):1870-5.
M Kaplitt; G K Gouras; H Makimura; J Jovanovic; D Sweeney; P Greengard; N R Relkin; S GandyAnnals of the New York Academy of Sciences 1996;802():42-9.
R Wang; D Sweeney; S E Gandy; S S SisodiaThe Journal of biological chemistry 1996;271(50):31894-902.
G B Van Setten; L Nilsson; S Hahne; J A Johnston; A Kvanta; S E Gandy; J Näslund; C NordstedtInvestigative ophthalmology & visual science 1996;37(13):2585-93.
A Doan; G Thinakaran; D R Borchelt; H H Slunt; T Ratovitsky; M Podlisny; D J Selkoe; M Seeger; S E Gandy; D L Price; et al.Neuron 1996;17(5):1023-30.
N Y Calingasan; S E Gandy; H Baker; K F Sheu; J D Smith; B T Lamb; J D Gearhart; J D Buxbaum; C Harper; D J Selkoe; et al.The American journal of pathology 1996;149(3):1063-71.
G Thinakaran; D R Borchelt; M K Lee; H H Slunt; L Spitzer; G Kim; T Ratovitsky; F Davenport; C Nordstedt; M Seeger; et al.Neuron 1996;17(1):181-90.
H Xu; D Sweeney; P Greengard; S GandyProceedings of the National Academy of Sciences of the United States of America 1996;93(9):4081-4.
R N Martins; B A Turner; R T Carroll; D Sweeney; K S Kim; H M Wisniewski; J P Blass; G E Gibson; S GandyNeuroreport 1995;7(1):217-20.
H Xu; P Greengard; S GandyThe Journal of biological chemistry 1995;270(40):23243-5.
D L Price; S S Sisodia; S E GandyCurrent opinion in neurology 1995;8(4):268-74.
J Näslund; J Thyberg; L O Tjernberg; C Wernstedt; A R Karlström; N Bogdanovic; S E Gandy; L Lannfelt; L Terenius; C NordstedtNeuron 1995;15(1):219-28.
N Y Calingasan; S E Gandy; H Baker; K F Sheu; K S Kim; H M Wisniewski; G E GibsonBrain research 1995;677(1):50-60.
H Zhang; H Komano; R S Fuller; S E Gandy; D E FrailThe Journal of biological chemistry 1994;269(45):27799-802.
C C Ouimet; K D Baerwald; S E Gandy; P GreengardThe Journal of comparative neurology 1994;348(2):244-60.
S GandyNeurobiology of aging 1994;15(4):471-2; discussion 473.
A B Jaffe; C D Toran-Allerand; P Greengard; S E GandyThe Journal of biological chemistry 1994;269(18):13065-8.
G L Caporaso; K Takei; S E Gandy; M Matteoli; O Mundigl; P Greengard; P De CamilliThe Journal of neuroscience : the official journal of the Society for Neuroscience 1994;14(5 Pt 2):3122-38.
C Nordstedt; J Näslund; J Thyberg; E Messamore; S E Gandy; L TereniusThe Journal of biological chemistry 1994;269(13):9805-10.
S GandyNeurobiology of aging 1994;15 Suppl 2():S157-60.
S Gandy; P GreengardBiochimie 1994;76(3-4):300-3.
S Gandy; P GreengardInternational review of neurobiology 1994;36():29-50.
J Knops; S Gandy; P Greengard; I Lieberburg; S SinhaBiochemical and biophysical research communications 1993;197(2):380-5.
O A da Cruz e Silva; K Iverfeldt; T Oltersdorf; S Sinha; I Lieberburg; T V Ramabhadran; T Suzuki; S S Sisodia; S Gandy; P GreengardNeuroscience 1993;57(4):873-7.
S E Gandy; G L Caporaso; J D Buxbaum; O de Cruz Silva; K Iverfeldt; C Nordstedt; T Suzuki; A J Czernik; A C Nairn; P GreengardAnnals of the New York Academy of Sciences 1993;695():117-21.
T V Ramabhadran; S E Gandy; J Ghiso; A J Czernik; D Ferris; R Bhasin; D Goldgaber; B Frangione; P GreengardThe Journal of biological chemistry 1993;268(3):2009-12.
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NATIONAL INSTITUTE ON AGING
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D J SelkoeNeurobiology of aging 1989;10(5):387-95.
E Levy; M D Carman; I J Fernandez-Madrid; M D Power; I Lieberburg; S G van Duinen; G T Bots; W Luyendijk; B FrangioneScience (New York, N.Y.) 1990;248(4959):1124-6.
F Tagliavini; J Ghiso; W F Timmers; G Giaccone; O Bugiani; B FrangioneLaboratory investigation; a journal of technical methods and pathology 1990;62(6):761-7.
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