Zusammenfassung
Die Alzheimer Erkrankung ist vor allem durch das Auftreten von Amyloidplaques im extrazellulären Raum des Gehirns gekennzeichnet (Selkoe, 1993). Die Krankheit tritt meist sporadisch auf. In einigen wenigen Fällen ( < 10%) kann die Alzheimer Erkrankung jedoch auch genetisch vererbt werden (Haass und Selkoe, 1993).
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Literatur
Alzheimer’s Disease Collaborative Group (1995) The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nature Genetics 11: 219–222
Baumeister R, Leimer U, Zweckbronner I, Jakubek C, Grünberg J, Haass C (1997) Human presenilin-1, but not familial Alzheimer’s disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing. Genes & Function 1: 149–159
Borchelt DR, Thinakaran G, Eckman CB et al. (1996) Familial Alzheimer’s disease-linked presenilin 1 variants elevate Aßl-42/1-40 ratio In Vitro and In Vivo. Neuron 17: 1005–1013
Busciglio J, Gabuzda DH, Matsudaira P, Yankner BA (1993) Generation of ß-amyloid in the secretory pathway in neuronal and nonneuronal cells. Proc Natl Acad Sei USA 90: 2092–2096
Cai XD, Golde T, Younkin S (1993) Release of excess amyloid ß protein from a mutant amyloid ß protein precursor. Science 259: 514–516
Capell A, Grünberg J, Pesold B et al. (1998) The proteolytic fragments of the Alzheimer’s disease-associated presenilin-1 form heterodimers and occur as a 100-150-kDa molecular mass complex. J Biol Chem 273: 3205–3211
Chen W, Goldstein J, Brown M (1990) NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein reeeptor. J Biol Chem 265: 3116–3123
Citron M, Oltersdorf T, Haass C et al. (1992) Mutation of the ß-amyloid precursor protein in familial Alzheimer’s disease increases ß-protein produetion. Nature 360: 672–674
Citron M, Westaway D, Xia W, et al. (1997) Mutant presenilins of Alzheimer’s disease increase produetion of 42-residue amyloid ß-protein in both transfected cells and transgenic mice. Nature Medicine 3: 67–72
Cook D, Forman M, Sung J et al. (1997) Alzheimer’s Aß (1-42) is generated in the endoplasmic reticulum/ intermediate compartment of NT2N cells. Nature Medicine 3: 1021–1023
Cook D, Sung J, Golde T et al. (1996) Expression and analysis of presenilin 1 in a human neuronal system: Localization in cell bodies and dendrites. Proc Natl Acad Sei USA 93: 9223–9228
De Strooper B, Beullens M, Contreras B et al. (1997) Phosphorylation, subcellular localization and membrane orientation of the Alzheimer’s disease-associated presenilins. J Biol Chem 272: 3590–3598
De Strooper B, Saftig P, Craessaerts K et al. (1998) Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391: 387–390
Doan A, Thinakaran G, Borchelt DR et al. (1996). Protein topology of presenilin 1. Neuron 17: 1023–1030
Duff K, Eckman C, Zehr C et al. (1996) Increased amyloid-ß42 (43) in brains of mice expressing mutant presenilin 1. Nature 383: 710–713
Estus S, Golde TE, Kunishita T et al. (1992) Potentially amyloidogenic, carboxyl-terminal derivatives of the amyloid protein precursor. Science 255: 726–728
Glenner G, Wong C (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120: 885–890
Golde T, Estus S, Younkin L, Selkoe D, Younkin S (1992) Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science 255: 728–730
Haass C(1996) The presenilin genes and early dementia. Current Opinion in Neurology 9: 254–259
Haass C (1997) Presenilins: Genes for life and death. Neuron 18: 687–690
Haass C, Hung AY, Selkoe DJ (1991) Processing of ß-amyloid precursor protein in microglia and astrocytes favors an internal localization over constitutive secretion. J Neuroscience 11: 3783–3793
Haass C, Hung AY, Schlossmacher M, Teplow D, Selkoe D (1993) ß amyloid peptide and a 3-kDa fragment are derived by distinct cellular mechanisms. J Biol Chem 268: 3021–3024
Haass C, Hung AY, Selkoe DJ, Teplow DB (1994b) Mutations associated with a locus for familial Alzheimer’s disease result in alternative processing of amyloid ß-protein precursor. J Biol Chem269: 1–8
Haass C, Koo E, Mellon A, Hung AY, Selkoe DJ (1992a) Targeting of cell-surface ß-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature 357: 500–503
Haass C, Lemere C, Capell A et al. (1995b) ß-secretase cleavage of ß-amyloid precursor protein with the Swedish mutation occurs within the secretory pathway after the trans-Golgi network. Nature Medicine 1:1291–1296
Haass C, Schlossmacher M, Hung AY et al. (1992b) Amyloid ß-peptide is produced by cultured cells during normal metabolism. Nature 359: 322–325
Haass C, Selkoe DJ (1993) Cellular processing of ß-amyloid precursor protein and the genesis of amyloid ß-peptide. Cell 75: 1039–1042
Haass C, Selkoe DJ (1998) A technical KO of amyloid-ß peptide. Nature 391: 339–340
Hartmann T, Bieger S, Brühl B et al. (1997) Distinct sites of intracellular production for Alzheimer’s disease Aß40/42 amyloid peptides. Nature Medicine 3: 1016–1020
Jarrett J, Lansbury P (1993) Seeding “one-dimensional chrystallization” of amyloid: a pathogenic mechanism in Alzheimer’s disease and scrapie? Cell 73: 1055–1058
Kang J, Lemaire HG, Unterbeck A et al. (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325: 733–736
Kovacs DM, Fausett HJ, Page KJ et al. (1996) Alzheimer-associated presenilins 1 and 2: Neuronal expression in brain and localization to intracellular membranes in mammalian cells. Nature Medicine 2: 224–229
Lemere C, Lopera F, Kosik K et al. (1996) The E280A presenilin 1 Alzheimer mutation produces increased Aß42 deposition and severe cerebellar pathology. Nature Medicine 2: 1146–1148
Levitan D, Doyle T, Brousseau D, Lee M, Thinakaran G, Slunt H, Sisodia S, Greenwald I (1996) Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. Proc Acad Sei USA 93: 14940–14944
Levitan D, Greenwald I (1995) Facilitation of lin-12-mediated signalling by SEL-12, a Caenorhabditis elegans S182 Alzheimer’s disease gene. Nature 377: 351–354
Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J et al. (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269: 973–977
Li X, Greenwald I (1996) Membrane topology of the C. elegans SEL-12 presenilin. Neuron 17: 1015–1021
Lorenzo A, Razzaboni B, Weir G, Yankner B (1994) Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus. Nature 368: 756–760
Mullan M, Crawford F (1993) Genetic and molecular advances in Alzheimer’s disease. TINS 16: 398–403
Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M et al. (1995) Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376: 775–778
Scheuner D, Eckman C, Jensen M, Song X, Citron M et al. (1996) Secreted amyloid ß-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nature Medicine 2: 864–870
Selkoe DJ (1993) Physiological production of the ß-amyloid protein and the mechanism of Alzheimer’s disease. Trends in Neurosci 16: 403–409
Seubert P, Vigo-Pelfrey C, Esch F, Lee M, Dovey H, Davis D, Sinha S et al. (1992) Isolation and quantification of soluble Alzheimer’s ß-peptide from biological fluids. Nature 359: 325–327
Schellenberg GD, Bird TD, Wijsman EM, Orr HT, Anderson L et al. (1992) Genetic linkage evidence for a familial Alzheimer disease locus on chromosome 14. Science 3: 1–4
Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G et al. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375: 754–760
Shoji M, Golde T, Hiso J, Cheung T, Estus S, Shaffer L et al. (1992) Production of the Alzheimer amyloid ß protein by normal proteolytic processing. Science 258: 126–129
Suzuki N, Cheung TT, Cai XD, Odaka A, Otvos L, Eckman C, Golde TE, Younkin SG (1994) An increased percentage of long amyloid ß protein secreted by familial amyloid ß protein precursor (ßAPP 7 n) mutants. Science 262: 1336–1340
Steiner H, Capell A, Pesold B et al. (1998) Expression of Alzheimer’s disease-associated presenilin-1 is controlled by proteolytic degradation and complex formation. J Biol Chem 273: 32322–32331
Thinakaran G, Borchelt D, Lee M, Slunt H, Spitzer L et al. (1996) Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17: 181–190
Tomita T, Maruyama K, Saido T et al. (1997) The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid ß protein ending at the 42nd (or 43rd) residue. Proc Natl Acad Sei USA 94, 2025–2030
Yankner B, Duffy L, Kirschner D (1990) Neurotrophic and neurotoxic effects of amyloid ß protein: Reversal by Tachykinin Neuropeptides. Science 250: 279–282
Walter J, Capell A, Grünberg J et al. (1996) The Alzheimer’s disease - associated presenilins are differentially phosphorylated proteins located predominantly within the endoplasmic reticulum. Molecular Medicine 2: 673–691
Walter J, Grünberg J, Capell A et al. (1997) Proteolytic processing of the Alzheimer disease-associated presenilin-1 generates an in vivo substrate for protein kinase C. Proc Natl Acad Sei USA 94: 5349–5354
Weidemann A, König G, Bunke D, Fischer P, Salbaum M, Masters C, Beyreuther K(1989) Identification, biogenesis, and localization of precursors of Alzheimer’s disease A4 amyloid protein. Cell 7: 115–126
Weidemann A, Paliga K, Dürrwang U, Czech C, Evin G, Masters C, Beyreuther K(1997) Formation of stable complexes between two Alzheimer’s disease gene produets: Presenilin-2 and ß-amyloid precursor protein. Nature Medicine 3: 328–332
Wild-Bode C, Yamazaki T, Capell A, Leimer U, Steiner H, Ihara Y, Haass C (1997) Intracellular generation and accumulation of amyloid ß-peptide terminating at amino acid 42. J Biol Chem 272: 16085–16088
Xia W, Zhang J, Kolodenko D et al. (1997a) Enhanced produetion and oligomerization of the 42-residue amyloid ß-protein by CHO cells stably expressing mutant presenilins. J Biol Chem 272: 7977–7982
Xia W, Zhang J, Perez R, Koo E, Selkoe D (1997b) Interaction between amyloid precursor protein and presenilins in mammalian cells: implications for the pathogenesis of Alzheimer’s disease. Proc Acad Sei USA 94: 8208–8213
Younkin S (1995) Evidence that Aß42 is the real culprit in Alzheimer’s Disease. Annais of Neurology 37: 287–288
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Haass, C. (1999). Molekulare Mechanismen der Alzheimer Erkrankung. In: Förstl, H., Bickel, H., Kurz, A. (eds) Alzheimer Demenz. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-60228-3_4
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DOI: https://doi.org/10.1007/978-3-642-60228-3_4
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