Molecular genetics of Alzheimer's disease

Nörodejeneratif bir hastalık olan Alzheimer hastalığı (AH) yaşlılarda en sık görülen demans tipidir. Çevresel etkenlerin yanı sıra, ileri yaş AH için bilinen en etkili risk faktörüdür. Olguların yüzde 90’ı 65 yaşın üzerinde ve sporadik olarak ortaya çıkar (Geç-Başlangıçlı AH, GBAH). Ancak hastalığın etiyolojisinde genetik faktörlerin etken olduğuna dair yeterince kanıt vardır. Bugüne kadar mutasyona uğradıklarında otozomal baskın seyreden, erken-başlangıçlı AH’ye (EBAH) neden olan üç gen tanımlanmıştır; β-Amiloid Prekörsır Protein (APP), Presenilin 1 (PSEN1) ve Presenilin 2 (PSEN2). Bunun yanı sıra, asosiyasyon analizleri yüzden fazla genin GBAH için risk faktörü oluşturduğunu göstermiştir. Ancak Apolipoprotein E geninin (APOE) E4 aleli günümüzde kesin kabul gören yegane risk faktörüdür. Birçok araştırmacı bağlantı ya da asosiyasyon analizleri ile AH bağlantılı kromozomal lokasyonlar bulmaya çalışmıştır. Tüm genom taramaları birçok değişik bölgeyi göstermiş olsa da, sadece birkaç bölge en az üç çalışmada da pozitif sonuç vermiştir. APP, PSEN ve APOE dışındaki diğer genlerin AH ile bağlantısının değişik toplumlarda da araştırılması gerekmektedir.

Alzheimer hastalığı'nın moleküler genetiği

Alzheimer's Disease (AD) is the most common neurodegenerative disorder that leads to dementia in the elderly. Besides environmental factors, age is the most common and effective risk factor for AD development. In more than 90 per cent of cases AD develops after the age of 65 years (late-onset AD, LOAD) the majority being sporadic. But there is enough of evidence that AD has a genetic etiology. The molecular mechanism that leads to AD is yet unclear, but, to date three genes are identified that when mutated cause autosomal dominant early-onset AD (EOAD). These are β-Amyloid Precursor Protein (APP), Presenilin 1 (PSEN1) and Presenilin 2 (PSEN2). In addition, more than 100 genes have been associated with LOAD, as risk factors. However, only the E4 allele of the Apolipoprotein E gene (APOE) is accepted as the single most common genetic determinant of susceptibility to AD. Many researchers have attempted to find chromosomal locations either by linkage or by association studies. Full genome screens revealed many different loci on different chromosomes, but only some of them yielded positive results in at least three independent studies. The association of genes other than APP, PSENs and APOE with AD needs further investigation in different populations.

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Ahmed AR, MacGowan SR, Culpan D, Jones RW, Wilcock GK. The -491A/T polymorphism of the apolipoprotein E gene is associated with the ApoE ε4 allele and Alzheimer's disease. Neuroscience Letters. 263:217-219, 1999.
Alzheimer's Disease Collaborative Group: Clark RB, Hutton M, Fuldner PA, Froelich S, Karran B, Talbot C, Crook R, Lendon C, Priliar G, He C, Korenblat K, Martinez A, Wragg M, Busfield B, Bebrens MI, Myers A, Norton J, Morris J, Mebta N, Pearson C, Lincoln C, Baker M, Duff K, Zelir C, Perez-Tur J, Houlden H, Ruir A, Ossa J, Lopera B, Arcos M, Madrigal L, Collinge J, Humphreys C, Ashworth A, Sarner S, Fox N, Harvey R, Kennedy A, Roques B,
Cline RI, Philips CA, Venter JC, Forsell L, Axelman K, Lilius L, Johnston J, Cowburn R, Vutanen M, Windblad B, Kosik K, Haltia M, Poyhonen M, Dickson D, Mann D, Near D, Snowdon J, Lantos P, Lannfelt L, Rossor M, Roberts GW, Adams MD, Hardy J, Goate A. The structure of the Presenilin 1 (8182) gene and identification of six novel mutations in earlyonset AD families. Nature Genetics. 11:219-222, 1995.
Amouyel P, Vidal O, Launay JM, Laplanche JL. The apolipoprotein E alleles as major susceptibility factors for Creutzfeldt-Jakob disease. Lancet. 344:1315-1318, 1994.
Annaert WG, Esselens C, Baert V, Boeve C, Snellings G, Cupers P, Craessaerts K, De Strooper B. Interaction with telencephalin and the amyloid precursor protein predicts a ring structure for presenilins. Neuron. 32:579–89,2001.
Anwar R, Moynihan TP, Ardley H, Brindle N, Coletta PL, Cairns N, Markham AF, Robinson P. Molecular analysis of the presenilin 1 (S182) gene in "sporadic" cases of Alzheimer's disease: identification and characterisation of unusual splice variants. Journal of Neurochemistry. 66:1774-1777, 1996.
Artiga MJ, Bullido MJ, Sastre I, Recuero M, Garcia MA, Aldudo J, Vazquez J, Valdivieso F. Allelic polymorphisms in the transcriptional regulatory region of apolipoprotein E gene. FEBS Letters.421:105-108, 1998.
Asai M, Hattori C, Szabo B, Sasagawa N, Maruyama K, Tanuma S, Ishiura S. Putative function of ADAM9, ADAM10, and ADAM17 as APP alpha-secretase. Biochemical Biophysical Research Communication. 301:231-235, 2003.
Baek SH, Ohgi KA, Rose DW, Koo EH, Glass CK, Rosenfeld MG. Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kappaB and beta- amyloid precursor protein. Cell. 110:55-67,2002.
Bakker E, Van Broeckhoven C, Haan J. DNA diagnosis for hereditary cerebral hemorrhage with amyloidosis (Dutch type). American Journal of Human Genetics. 49:518-521,1991.
Basu SK, Brown MS, Ho YK, Havel RJ, Goldstein JL. Mouse macrophages synthesize and secrete a protein resembling apoprotein E. Proceedings of National Academy of Sciences USA. 78:7545-7549, 1981.
Bauer J, Strauss S, Schreiter-Gasser U, Ganter U, Schlegel P, Witt I, Yolk B, Berger M. Interleukin- 6 and alpha 2-macroglobulin indicate an acute-phase state in Alzheimer's disease conices. FEBS Letters. 285:111-114, 1991.
Baumeister R, Haass C. The Molecular Biology of Alzheimer's Disease, Harwood Academic Publishers, Chur, 1998.
Bennett C, Crawford F, Osborne A, Diaz P, Hoyne J, Lopez R, Roques P, Duara R, Rossor M, Mullan M. Evidence that the APOE locus influences rate of disease progression in late onset familial Alzheimer's disease but is not causative. American Journal of Medical Genetics. 60:1-6, 1995.
Bertram L, Parkinson M, Mullin K, Menon R, Blacker D, Tanzi RE. No association between a previously reported OLR1 3' UTR polymorphism and Alzheimer's disease in a large family sample. Journal of Medical Genetics. 41:286-8, 2004.
Betard C, Robitaille Y, Gee M, Tiberghien D, Larrivee D, Roy P, Mortimer JA, Gauvreau D. Apo E allele frequencies in Alzheimer's disease, Lewy body dementia, Alzheimer's disease with cerebrovascular disease and vascular dementia. Neuroreport. 5:1893-1896, 1994.
Bhasin R, Van Nostrand WE, Saitoh T, Donets MA, Barnes EA, Quitschke WW, Goldgaber D. Expression of active secreted forms of human amyloid β protein precursor by recombinant baculovirus- infected insect cells. Proceedings of National Academy of Sciences USA. 88:10307- 10311, 1991.
Boerwinkle E, Visvikis S, Welsh D, Steinmetz J, Hanash SM, Sing CF. The use of measured genotype information in the analysis of quantitative phenotypes in man. II. The role of the apolipoprotein E polymorphis in determining levels, variability, and co variability cholesterol, betalipoprotein, and triglycerides in a sample unrelated individuals. American Journal of Medical Genetics. 27:567-582, 1989.
Bing Z, Reddy SA, Ren Y, Qin J, Liao WSL. Purification and charecterization of the serum amyloid A3 enhancer factor. Journal of Biological Chemistry. 274:24649-24656, 1999.
Breslow JL, Zannis VI, SanGiacomo TR, Third JL, Tracy T, Glueck CJ. Studies of familial type III hyperlipoproteinemia using as a genetic marker the apoE phenotype E2/2. Journal of Lipid Research. 23:1224-1235, 1982.
Breteler MMB, Claus JJ, Van Dujin CM. Epidemiology of Alzheimer's Disease. Epidemiology Review. 14:59-82, 1992.
Brockhau M, Grunberg J, Rohrig S, Loetscher H, Wittenburg N, Baumeister R, Jacobsen H, Haass C. Caspase-mediated cleavage is not required for the activity of presenilins in amyloidogenesis and NOTCH signaling. Neuroreport. 9:1481-1486, 1998.
Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, Cumano A, Roux P, Black RA, Israel A. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin- metalloprotease TACE. Molecular Cell. 5:207-216, 2000.
Buee L, Ding W, Delacourte A, Flint H. Binding of secreted human neuroblastoma proteoglycans to the Alzheimer's amyloid A4 peptide. Brain Research. 601:154-163, 1993.
Bullido MJ, Artiga MJ, Recuero M, Sastre I, Garcia MA, Aldudo J, Lendon C, Han SW, Morris JC, Frank A. A polymorphism in the regulatory region of APOE associated with risk for Alzheimer's dementia. Nature Genetics. 18:69-71, 1998.
Campion P, Flaman J-M, Brice A, Hannequin D, Dubois B, Martin C, Moreau V, Charbonnier F, Didierjean O, Tardieu S, Penet C, Puel M, Pasquict F, Bellis G, Calenda A, Heilig R, Martinez M, Mallet J, Bellis M, Clerget- Darpoux F, Agid Y, Frebourg T. Mutations of the Presenilin- I gene in families with earlyonset Alzheimer's disease. Human Molecular Genetetics. 4:2373-2377, 1995.
Cao X, Sudhof TC. A transcriptionally (correction of transcriptively) active complex of APP with Fe65 and histone acetyltransferase Tip60. Science. 293:115-20, 2001.
Chen L, Baum L, Ng HK, Chan LY, Sastre J, Artiga MJ, Valdivieso F, Bullido MJ, Chiu HF, Pang CP. Apolipo-protein F promoter and α2-macroglobulin polymorphisms are not genetically associated with Chinese late onset Alzheimer's disease. Neuroscience Letters. 269:173-177, 1999.
Clarimon J, Bertranpetit J, Calafell F, Boada M, Tarraga L, Comas D. Association study between Alzheimer’s disease and genes involved in Abeta biosynthesis, aggregation and degradation: suggestive results with BACE1. Journal of Neurology. 250:956–961, 2003.
Claus JJ, Breteler MM, Hasan D, Krenning EP, Bots ML, Grobbee DE, Van Swieten JC, Van Harskamp F, Hofman A. Regional cerebral blood flow and cerebrovascular risk factors in the elderly population. Neurobiology of Aging. 19:57-64, 1998.
Cohen ML. Golde TE, Usiak MF, Younkin LH, Vounkin SG. In situ hybridization of nucleus basalis neurons shows increased β-amyloid mRNA in Alzheimer's disease. Proceeding of National Academy of Sciences USA. 85:1227- 1231, 1988.
Colacicco AM, Panza F, Basile AM, Solfrizzi V, Capurso C, D'Introno A, Torres F, Capurso S, Cozza S, Flora R, Capurso A. F175S change and a novel polymorphism in presenilin-1 gene in late-onset familial Alzheimer's disease. European Neurology. 47:209-213, 2002.
Cook, DG, Sung JC, Golde TE, Felsenstein KM, Wojczyk BS, Tanzi RE, Trojanowskij Q, Lee VM, Doms RW. Expression and analysis of presenilin 1 in a human neuronal system: Localization in cell bodies and dentrites. Proceedings of National Academy of Sciences. 93:9223-9228, 1996.
Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PCJr, Rimmler JB, Locke PA, Conneally PM, Schmader KE, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nature Genetics. 7:180-184, 1994.
Crook R, Verkkoniemi A, Perez-Tur J, Mehta N, Baker M, Houlden H, Farrer M, Hutton M, Lincoln S, Hardy J, Gwinn K, Somer M, Paetau A, Kalimo H, Ylikoski R, Poyhonen M, Kucera S, Haltia M. A variant of Alzheimer’s disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nature Medicine. 4:452–455, 1998.
Cruts M, Backhovens H, Wang S-Y, Van Gassen G, Theuns J, De Jooghe C, Wehnert A, De Voecht J, De Winter G, Cras P, Broyland M, Datson N, Weissenbach J, den Dunnen J, Martin JJ, Hendriks L, Van Broeckhoven C. Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. Human Molecular Genetics. 4:2363-2372, 1995.
Cruts M, Hendriks L, Van Broeckhoven C. The presenilin genes:A new gene family involved in Alzheimer disease pathology. Human Molecular Genetics. 5:1449-1455, 1996.
Cruts M, van Duijn CM, Backhovens H, Van den Broeck M, Wehnert A, Serneels S, Sherringron R, Hutton M, Hardy J, St George-Hyslop PH, Hofman A, Van Broeckhoven C. Estimation of the genetic contribution of presenilin- I and -2 mutations in a population-based study of presenile Alzheimer disease. Human Molecular Genetics. 7:43-51, 1998.
Cruts M. AD and FTD Mutation database, 2007, http://www.molgen.ua.ac.be/ADMutations/ Culpan D, MacGowan SH, Ford JM, Nicoll JA, Griffin WS, Dewar D, Cairns NJ, Hughes A, Kehoe PG Wilcock GK. Tumour necrosis factor- alpha gene polymorphisms and Alzheimer’s disease. Neuroscience Letters. 350:61–65, 2003.
Cummings JL. Dementia: the failing brain. Lancet. 345:1481-1489, 1995.
Daigle I, Li C. apI-1, a C. elegans gene encoding a protein related to the human beta-amyloid protein precursor. Proceeding of National Academy of Sciences USA. 90:12045-12049,1993.
Davignon J, Gregg RE, Sing CF. Apolipoprotein E polymorphism and atherosclerosis. Atherosclerosis. 8:1-21, 1988.
Dermaut B, Roks G, Theuns J, Rademakers R, Houwing-Duistermaat JJ, Serneels S, Hofman A, Breteler MM, Cruts M, Van Broeckhoven C, Van Duijn CM. Variable expression of presenilin 1 is not a major determinant of risk for late-onset Alzheimer’s disease, Journal of Neurology. 248:935–939, 2001.
Di Natale M, Perri M, Kawarai T, Maletta R, Tomaino C, Sato C, Nacmias B, Shibata N, Sorbi S, St George-Hyslop P, Bruni AC, Rogaeva E. Absence of association between Alzheimer disease and the regulatory region polymorphism of the PS2 gene in an Italian population. Neuroscience Letters. 343:210-212, 2003.
Doan A, Thinakaran G, Borchelt DR, Slunt HH, Ratovirskyl Podlisny M, Selkoe DJ, Seeger M, Gandy SE, Price DL, Sisodia SS. Protein topology of presenilin 1. Neuron. 17:1023-1030, 1996.
Du Y, Ni B, Glinn M, Dodel RC, Bales KR, Zhang Z, Hyslop PA, Paul SM. Alpha 2- macroglobulin as a beta-amyloid peptidebinding plasma protein. Journal of Neurochemistry. 69:299-305, 1997.
Duara R, Lopez-Alberola RF, Barker WW. A comparison of familial and sporadic Alzheimer's disease. Neurology. 3:1377-1384, 1993.
Edland SD, Wavrant-De Vriese F, Compton D, Smith GE, Ivnik R, Boeve BF, Tangalos EG, Petersen RC. Insulin degrading enzyme (IDE) genetic variants and risk of Alzheimer’s disease: evidence of effect modification by apolipoprotein E (APOE). Neuroscience Letters. 345:21–24, 2003.
Elshourbagy NA, Liao WS, Mahley RW, Taylor JM. Apolipoprotein E mRNA is abundant in the brain and adrenals as well as in the liver, and is present in other peripheral tissues of rat and marmosets. Proceedings of National Academy of Sciences USA. 82:203-207, 1985.
Esch FS, Keim PS, Beattie EC, Blacher RW, Cuiwell AR, Oltersdorf T, McClure D, Ward PJ. Cleavage of amyloid β peptide during constitutive processing of its precursor. Science. 248:1122-1124, 1990.
Evans KC, Berger EP, Cho CG, Weisgraber KH, Lansbury PTJr. Apolipoprotein E is a kinetic but not a thermodynamic inhibitor of amyloid formation: implications for the pathogenesis and treatment of Alzheimer disease. Proceedings of National Academy of Sciences USA. 92:763-767, 1995.
Fagan AM, Bu G, Sun Y, Daugherty A, Holtzman DM. Apolipoprotein E-containing high density lipoprotein promotes neurite outgrowth and is a ligand for the low density lipoprotein receptorrelated protein. Journal of Biological Chemistry. 271:30121-30125, 1996.
Farrer LA, Bowirrat A, Friedland RP, Waraska K, Korczyn AD, Baldwin CT. Identification of multiple loci for Alzheimer disease in a consanguineous Israeli–Arab community. Human Molecular Genetics. 12:415–422, 2003.
Feuk L, Prince JA, Blennow K, Brookes AJ. Further evidence for role of a promoter variant in the TNFRSF6 gene in Alzheimer disease. Human Mutation. 21:53–60, 2003.
Fraser PE, Nguyen JT, McLachlan DR, Abraham CR, Kirschner DA. Alpha 1-antichymotrypsin binding to Alzheimer A beta peptides is sequence specific and induces fibril disaggregation in vitro. Journal of Neurochemistry, 61:298-305, 1993.
Georgakopoulos A, Marambaud P, Efthimiopoulos S, Shioi J, Cui W, Li HC, Schutte M, Gordon R, Holstein GR, Martinelli G, Mehta P, Friedrich VL Jr, Robakis NK. Presenilin-1 forms complexes with the cadherin/catenin cell-cell adhesion system and is recruited to intercellular and synaptic contacts. Molecular Cell. 4:893–902, 1999.
Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 349:704-706, 1991.
Goedert M. Neuronal localization of amyloid 13 protein precursor mRNA in normal human brain and in Alzheimer's disease. EMBO Journal. 6:3627-3632, 1987.
Golde TE, Estus S, Younkin LH, Selkoe DJ, Younkin SG. Processing of the amyloid protein precursor to potentially amyloidogenic carboxyl-terminal derivatives. Science. 255:728-730, 1992.
Greenberg S M, Rebeck GW, Vonsattel JPG, Gomez-Isla T, Hyman BT. Apolipoprotein E epsilon-4 and cerebral hemorrhage associated with amyloid angiopathy. Annals of Neurology. 38:254-259, 1995.
Guo Q, Furukawa K, Sopher BL, Pham DG, Xie J, Robinson N, Martin GM, Mattson MP. Alzheimer’s PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid β-peptide. Neuroreport. 8:379–83, 1996.
Haass C, Koo EM, Mellon A, Hung AY, Selkoe DJ. Targeting of cell-surface beta-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature. 357:500-503, 1992.
Haass C. Presenilins: genes for life and death. Neuron. 18:687-690, 1997.
Haines JL, Bailey R, Grubber JM, et al. A genomic research for Alzheimer’s disease genes. In: Alzheimer’s Disease: Advances in Etiology, Pathogenesis and Therapeutics (eds. K. Iqbal, S.S. Sisodia and B. Winblad), pp. 33-43.
Chichster: John Wiley and Sons. 2001. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the US population: prevalence estimates using the 2000 census. Archives of Neurology. 60:1119-22,2003.
Hendriks L, van Dujin CM, Cras P, Cruts M, Van Hul W, van Harskamp F, Warren A, McInnis MG, Antonarakis SE, Martin JJ. Presenile dementia and cerebral hemorrhage linked to a mutation at codon 692 of the β-amyloid precursor protein gene. Nature Genetics. 1:218-221,1992.
Herms J, Schneider I, Dewachter I, Caluwaerts N, Kretzschmar H, Van Leuven F. Capacitive calcium entry is directly attenuated by mutant presenilin- 1, independent of the expression of the amyloid precursor protein. Journal of Biological Chemistry. 278:2484–9, 2003.
Herz J. The LDL-receptor-related protein-portrait of a multifunctional receptor. Current Opinion in Lipidology. 4:107-113, 1993.
Hiltunen M, Mannermaa A, Thompson D, Easton D, Pirskanen M, Helisalmi S, Koivisto AM, Lehtovirta M, Ryynanen M, Soininen H. Genome- wide linkage disequilibrium mapping of late-onset Alzheimer’s disease in Finland. Neurology. 57:1663–1668, 2001.
Hofman A, Ott A, Breteler MMB. Ateroscelerosis, apolipoprotein E and the prevalance of dementia and Alzheimer's disease in a populationbased study: the Rotterdam study. Lancet. 349:151-154, 1997.
Holtzman D, Pitas R E, Kilbridge J, Nathan B, Mahley, RW, Bu G, Schwartz AL. Low density lipoprotein receptor related protein mediates apolipoprotein E-dependent neurite outgrowth in a central nervous system-derived cell line. Proceedings of National Academy of Sciences USA. 92:9480-9484, 1995.
Houlden H, Crook R, Backhovens H, Prihar G, Baker M, Hutton M, Rossor M, Martin JJ, Van Broeckhoven C, Hardy J. ApoE genotype is a risk factor in nonpresenilin early-onset Alzheimer's disease families. American Journal of Medical Genetics. 81:117-121, 1998.
Hutton M, Busfield F, Wragg M, Crook R, Perez- Tur J, Clark RF, Prihar C, Talbot C, Phillips H, Wright K, Baker M, Lendon C, Duff K, Martinez A, Houlden H, Nichols A., Karran E, Roberts C, Venter JC, Adams MD, Cline RI, Phillips CA, Fuldner RA, Hardy J, Goate A. Complete analysis of the presenilin 1 gene in families with early onset Alzheimer's disease. Neuroreport. 7:801-805, 1996.
Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y. Visualization of A beta 42(43) and Aβ40 in senile plaques with end- specific Aβ monoclonals: evidence that an initially deposited species is Aβ42(43). Neuron. 13:45-53, 1994.
Iwatsubo T, Mann DM, Odaka A, Suzuki N, Ihara Y. Amyloid beta protein (A beta) deposition: A beta 42(43) precedes A beta 40 in Down syndrome. Annals of Neurology. 37:294-299, 1995.
Johansson A, Hampel H, Faltraco F, Buerger K, Minthon L, Bogdanovic N, Sjogren M, Zetterberg H, Forsell L, Lilius L, Wahlund LO, Rymo L, Prince JA, Blennow K. Increased frequency of a new polymorphism in the cell division cycle 2 (cdc2) gene in patients with Alzheimer’s disease and frontotemporal dementia. Neuroscience Letters. 340:69–73,2003.
Kalaria R, Bhatti S, Palatinsky E, Pennington D, Shelton E, Chan H, Perry G, Lust W. Accumulation of the β amyloid precursor protein at sites of ischemic injury in rat brain. Neuroreport. 4:211-214, 1991.
Kamboh MI, Sangera DK, Ferrel RE, DeKosky ST. APOE*4-associated Alzheimer's disease risk is is modified by α1-antichymotrypsin polymorphism. Nature Genetics. 10:486-488,1995.
Kang J, Müller-Hill B. Differential splicing of Alzheimer's disease amyloid A4 precursor RNA in rat tissues: PreA4695 mRNA is predominantly produced in rat and human brain. Biochemical And Biophysical Research Communications. 166:1192-1200, 1990.
Kehoe P, Wavrant-De Vrieze F, Crook R, Wu WS, Holmans P, Fenton I, Spurlock G, Norton N, Williams H, Williams N. Lovestone S, Perez-Tur J, Hutton M, Chartier-Harlin MC, Shears S, Roehl K, Booth J, Van Voorst W, Ramic D, Williams J, Goate A, Hardy J, Owen MJ. et al. A full genome scan for late onset Alzheimer’s disease. Human Molecular Genetics. 8:237–245, 1999.
Ki CS, Na DL, Kim HJ, Kim JW. Alpha-1 antichymotrypsin and alpha-2 macroglobulin gene polymorphisms are not associated with Korean late-onset Alzheimer's disease. Neuroscience Letters. 302:69-72, 2001.
Kim TW, Pettingell WH, Hallmark O, Moir RD, Wasco W, Tanzi RE. Endoproteolytic cleavage and proteasomal degradation of presenilin 2 in transfected cells. Journal of Biological Chemistry. 272:11006-11010, 1997a.
Kim TW, Pettingell WH, Jung YK, Kovacs DM, Tanzi RE. Alternative cleavage of Alzheimerassociated presenilins during apoptosis by a caspase-3 family protease. Science. 277:373-376, 1997b.
Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ. γ-Secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proceeding of National Academy of Sciences USA. 100:6382–7, 2003.
Kirschling CM, Kolsch H, Frahnert C, Rao ML, Maier W, Heun R. Polymorphism in the BACE gene influences the risk for Alzheimer’s disease. Neuroreport. 14:1243–1246, 2003.
Kitaguchi N, Takahashi Y, Tokushima Y, Shiojiro S, Ito H. Novel precursor of Alzheimer's disease amyloid protein shows protease inhibitory activity. Nature. 331:530-532, 1988.
Kehoe PG, Russ C, McIlory S, Williams H, Holmans P, Holmes C, Liolitsa D, Vahidassr D, Powell J, McGleenon B, Liddell M, Plomin R, Dynan K, Williams N, Neal J, Cairns NJ, Wilcock G, Passmore P, Lovestone S, Williams J, Owen MJ. Variation in DCP1; encoding ACE; is associated with susceptibility to Alzheimer disease, Nature Genetics. 21:71–72, 1999.
Koudinov AR, Koudinova NV, Kumar A, Beavis RC, Ghiso J. Biochemical characterization of Alzheimer's soluble amyloid beta protein in human cerebrospinal fluid: association with high density lipoproteins. Biochemical And Biophysical Research Communications. 223:592-597, 1996.
Kounnas M, Moir R, Rebeck G, Bush A, Argraves W, Tanzi R, Hyman BT, Strickland D. LDL receptor- related protein: A multifunctional ApoE receptor. binds secreted β-amyloid precursor protein and mediates its degradation. Cell. 82:331-340, 1995.
Kovacs DM, Fausett HJ, Page KJ, Kim I, Moir RD, Merriam DE, Hollister RD, Hallmark CC, Mancini R, Felsenstein KM, Haan BI, Tanzi RE, Wasco W. Alzheimer-associated presenilins 1 and 2: Neuronal expression in brain and localization to intracellular membranes in mammlian cells. Nature Medicine. 2:224-229,1996.
König G, Mönning U, Czech C, Prior R, Banati R, Schreiter-Gasser U, Bauer J, Masters CL, Beyreuther K. Identification and differential expression of a novel alternative splice isoforms of the βA4 amyloid precursor protein (APP) mRNA in leukocytes and brain microglial cells. Journal of Biological Chemistry. 267:10804- 10809, 1992.
Kwok JBJ, Taddei K, Hallupp M, Fisher C, Brooks WS, Brue CA, Hardy J, Fulham MJ, Nicholson CA, Stell R, St George-Hyslop PH, Fraser PE, Kakulas B, Clarnette R, Relkin N, Candy SE, Schofield PR, Martins RN. Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and pre-liminary evidence for association of presenilin- 1 mutations with a novel phenotype. Neuroreport. 8:1537-1542, 1997.
La Du MJ, Pederson TM, Frail DB, Reardon CA, Getz GS, Falduto MT. Purification of apolipoprotein E attenuates isoform-specific binding to β-amyloid. Journal of Biological Chemistry. 270:9030-9042, 1995.
Lambert JC, Perez-Tur J, Dupire MJ, Galasko D, Mann D, Amouyel P, Hardy J, Delacourte A, Chartier-Harlin MC. Distortion of allelic expression of apolipoprotein E in Alzheimer's disease. Human Molecular Genetics. 6:2151-2154, 1997.
Lambert JC, Berr C, Pasquier F, Delacourte A, Frigard B, Cottel D, Perez-Tur J, Mouroux V, Mohr M, Cecyre D, Galasko D, Lendon C, Poirier J, Hardy J, Mann D, Amouyel P, Chartier- Harlin MC. Pronounced impact of Thl/11147cs mutation compared with -491 AT mutation on neural APOE gene expression and risk of developing Alsheimer's disease. Human Molecular Genetics. 7:1511-1516, 1998.
Lambert JC, Goumidi L, Vrieze FW, Frigard B, Harris JM, Cummings A, Coates J, Pasquier F, Cottel D, Gaillac M, St Clair D, Mann DM, Hardy J, Lendon CL, Amouyel P, Chartier- Harlin MC. The transcriptional factor LBP- 1c/CP2/LSF gene on chromosome 12 is a genetic determinant of Alzheimer's disease. Human Molecular Genetics. 9:2275-80, 2000.
Lambert JC, Luedecking-Zimmer E, Merrot S, Hayes A, Thaker U, Desai P, Houzet A, Hermant X, Cottel D, Pritchard A, Iwatsubo T, Pasquier F, Frigard B, Conneally PM, Chartier- Harlin MC, DeKosky ST, Lendon C, Mann D, Kamboh MI, Amouyel P. Association of 3'-UTR polymorphisms of the oxidised LDL receptor 1 (OLR1) gene with Alzheimer's disease. Journal of Medical Genetics. 40:424-30, 2003.
Laws SM, Taddei K, Martins G, Paton A, Fisher C, Clarnette R, Hallmayer J, Brooks WS, Gandy SF, Martins RN. The -491AA polymorphism in the APOE gene is associated with increased plasma apoE levels in Alzheimer's disease. Neuroreport. 10:879-882, 1999.
Lee JH, Mayeux R, Mayo D, Mo J, Santana V, Williamson J, Flaquer A, Ciappa A, Rondon H, Estevez P, Lantigua R, Kawarai T, Toulina A, Medrano M, Torres M, Stern Y, Tycko B, Rogaeva E, St George-Hyslop P, Knowles JA. Fine mapping of 10q and 18q for familial Alzheimer's disease in Caribbean Hispanics. Molecular Psychiatry. 9:1042-51, 2004.
Lehmann DJ, Johnston C, Smith AD. Synergy between the genes for butyrylcholinesterase K variant and apolipoprotein E4 in late-onset confirmed Alzheimer's disease. Human Molecular Genetics. 6:1933-1936, 1997.
Levy-Lahad E, Poorkaj P, Wang K, Hui Fu N, Oshima J, Mulligan J, Schellenberg CD. Genomic structure and expression of STM2, the chromosome 1 familial Alzheimer's disease gene. Genomics. 34:198-204, 1996.
Li YM, Xu M, Lai MT, Huang Q, Castro JL, Di- Muzio-Mower J, Harrison T, Lellis C, Nadin A, Neduvelil JG, Register RB, Sardana MK, Shearman MS, Smith AL, Shi XP, Yin KC, Shafer JA, Gardell SJ. Photoactivated γ- secretase inhibitors directed to the active site covalently label presenilin 1. Nature. 405:689–94, 2000.
Li YJ, Oliveira SA, Xu P, Martin ER, Stenger JE, Scherzer CR, Hauser MA, Scott WK, Small GW, Nance MA, Watts RL, Hubble JP, Koller WC, Pahwa R, Stern MB, Hiner BC, Jankovic J, Goetz CG, Mastaglia F, Middleton LT, Roses AD, Saunders AM, Schmechel DE, Gullans SR, Haines JL, Gilbert JR, Vance JM, Pericak- Vance MA, Hulette C, Welsh-Bohmer KA. Gluthione S-tranferase omega-1 modifies ageat- onset of Alzheimer disease and Parkinson disease. Human Molecular Genetics. 12:3259-3267, 2003.
Liao A, Nitsch RM, Greenberg SM, Finckh U, Blacker D, Albert M, Rebeck GW, Gomez-Isla T, Clatworthy A, Binetti G, Hock C, Mueller- Thomsen T, Mann U, Zuchowski K, Beisiegel U, Staehelin H, Growdon JH, Tanzi RE, Hyman BT. Genetic association of an alpha2- macroglobulin (Val1000lle) polymorphism and Alzheimer's disease. Human Molecular Genetics. 12:1953-6, 1998.
Lippa CF, Saunders AM, Smith TW. Familial and sporadic Alzheimer's disease: neuropathology cannot exclude a final common pathway. Neurology. 46:406-412, 1996.
Loetscher H, Deuschle U, Brockhaus M, Reinhardt D, Nelboeck P, Mous J, Grunberg J, Haass C, Jacobsen H. Presenilins are processed by caspase-type proteases. Journal of Biological Chemistry. 272:20655-20659,1997.
Lovestone S, Williams J, Owen MJ, Hardy J, Goate A. Full genome screen for Alzheimer’s disease: stage II analysis. American Journal of Medical Genetics. 71:154-61, 2002.
Lucotte G, Loirat F, Hazout S. Pattern of gradient of apolipoprotein E allele ε4 frequencies in western Europe. Human Biology. 69:253-262, 1997.
Luedecking-Zimmer K, DeKosky ST, Nebes R, Kamboh MI.Association of the 3’UTR transcription factor LBP-1c/CP2/LSF polymorphism with late-onset Alzheimer’s disease. American Journal of Medical Genetics (Neuropsychiatric Genetics). 117B:114-117, 2003.
Lusis AJ, Heinzmann C, Sparkes RS, Scott J, Knott TJ, Geller R, Sparkes MC, Mohandas T. Regional mapping of human chromosome 19: organization of genes for plasma lipid transport (APOC1, -C2, and -E and LDLR) and the genes C3, PEPD, and GPI. Proceedings of National Academy of Sciences USA. 83:3929-3933, 1986.
Mahley RW. Apolipoprotein E: Cholesterol transport protein with expanding role in cell biology. Science. 240:622-628, 1988.
Marambaud P, Shioi J, Serban G, Georgakopoulos A, Sarner S, Nagy V, Baki L, Wen P, Efthimiopoulos S, Shao Z, Wisniewski T, Robakis NK. A presenilin-1/γ-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J. 21:1948–56, 2002.
Matthijs G, Marynen P. A deletion polymorphism in the human alpha-2-macroglobulin (A2M) gene. Nucleic Acids Research. 19:5102, 1991.
Matthijs G, Devriendt K, Caissman J-J, Van Der Berghe H, Marynen P. Structure of the human alpha-2 macroglobulin gene and its promotor. Biochemical and Biophysical Research Communications. 184:596-603, 1992.
Mattson MP, Cheng B, Cuiwell AB, Esch FS, Lieberburg I, Rydel RE. Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the β-amyloid precursor protein. Neuron. 10:243-254, 1993.
Mayeux R, Stem Y, and Ottman R. The apolipoprotein ε4 allele in patients with Alzheimer's disease. Annals of Neurology. 34:752-754,1993.
McKhann G, Drachman D, Foistein M. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease. Neurology. 34:39-44, 1984.
McMillan PJ, Leverenz JB, Dorsa DM. Specific downregulation of presenilin 2 gene expression is prominent during early stages of sporadic late-onset Alzheimer's disease. Brain Research, Molecular Brain Research. 78:138-45, 2000.
Mirra SS, Heyman A, McKeel D. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology. 41:479-486, 1991.
Montoya SE, Aston CE, DeKosky ST, Kamboh MI, Lazo JS, Ferrell RE. Bleomycin hydrolase is associated with risk of sporadic Alzheimer's disease. Nature Genetics. 18:211-212, 1998.
Myers A, Wavrant De-Vrieze F, Holmans P, Hamshere M, Crook R, Compton D, Marshall H, Meyer D, Shears S, Booth J, Ramic D, Knowles H, Morris JC, Williams N, Norton N, Abraham R, Kehoe P, Williams H, Rudrasingham V, Rice F, Giles P, Tunstall N, Jones L, Lovestone S, Williams J, Owen MJ, Hardy J, Goate A. Full genome screen for Alzheimer’s disease: stage II analysis. American Journal of Medical Genetics. 71:154-61, 2002.
Narindrasorasak S, Lowery DE, Altman RA, Gonzalez- DeWhitt P, Greenberg BD, Kisilevsky R. Characterization of high affinity binding between laminin and Alzheimer's disease amyloid precursor proteins. Laboratory Investigation. 67:643-652, 1992.
Nathan BP, Bellosta S, Sanan DA, Weisgraber KH, Mahley RW, Pitas RE. Differential effects of apolipoprotein E3 and E4 on neuronal growth in vitro. Science. 264:850-852, 1994.
Neve RL, Finch EA, Dawes LR. Expression of the Alzheimer amyloid precursor gene transcripts in the human brain. Neuron. 1:669-677, 1988.
Nishimura M, Yu G, Levesque G, Zhang DM, Ruel L, Chen F, Milman P, Holmes E, Liang Y, Kawarai T, Jo E, Supala A, Rogaeva E, Xu DM, Janus C, Levesque L, Bi Q, Duthie M, Rozmahel R, Mattila K, Lannfelt L, Westaway D, Mount HT, Woodgett J, St George- Hyslop P, et al. Presenilin mutations associated with Alzheimer disease cause defective intracellular trafficking of β-catenin, a component of the presenilin protein complex. Nature Medicine. 5:164–9, 1999.
Noll E, Medina M, Hartley D, Zhou J, Perrimon N, Kosik KS. Presenilin affects arm/β-catenin localization and function in Drosophila. Developmental Biology. 227:450–64, 2000.
Oesriendt K, Zhang L, Van Lenven F, Van den Berghe H, Cassiman JJ, Marynen P. A cluster of alpha 2-macroglobulin-related genes (alpha 2 M) on human chromosome 12p: cloning of the pregnancy-zone protein gene and an alpha 2M pseudogene. Gene. 81:325-354, 1989.
Okuizumi K, Onodera O, Namba Y, Ikeda K, Yamamoto T, Seki K, Ueki A, Nanko S, Tanaka H, Takahashi H. Genetic association of the very low density lipoprotein (VLDL) receptor gene with sporadic Alzheimer's disease. Nature Genetics. 11:207-209, 1995.
Ott A, Slooter AJC, Hofinan A. Smoking and the risk of dementia and Alzheimer's disease in a population-based cohort study: the Rotterdam study. Lancet. 351:1840-1843, 1998.
Paik YK, Chang DJ, Reardon CA, Davies GE, Mahley RW, Taylor JM. Nucleotide sequence and structure of the human apolipoprotein E gene. Proceedings of National Academy of Sciences USA. 82:3445-3449, 1989.
Passer BJ, Pellegrini L, Vito P, Ganjei JK, D'Adamio L. Interaction of Alzheimer's presenilin- 1 and presenilin-2 with Bcl-X(L). A potential role in modulating the threshold of cell death. Journal of Biological Chemistry. 274:24007-13, 1999.
Pericak-Vance MA, Grubber J, Bailey LR, Hedges D, West S, Santoro L, Kemmerer B, Hall JL, Saunders AM, Roses AD, Small GW, Scott WK, Conneally PM, Vance JM, Haines JL. Identification of novel genes in late-onset Alzheimer’s disease. Experimental Gerontology. 35:1343–52, 2000.
Pillot T, Goethals M, Vanloo B, Lins L, Brasseur R, Vandekerckhove J, Rosseneu M. Specific modulation of the fusogenic properties of the Alzheimer beta-amyloid peptide by apolipoprotein E isoforms. European Journal of Biochemistry. 243:650-659, 1997.
Pirskanen M, Alafuzoff I, Hiltunen M, Mannermaa A, Helisalmi S, Lehtovirta M, Koivisto AM, Laakso M, Soininen H. An association between a subset of Finnish late-onset Alzheimer's disease and alpha2-macroglobulin.Neurogenetics. 3:171-2, 2001.
Pitas RE, Boyles JK, Lee SH, Hui D, Weisgraber KH. Lipoproteins and their receptors in the central nervous system. Characterization of the lipoproteins in cerebrospinal fluid and identification of apolipoprotein B, E (LDL) receptors in the brain. Journal of Biological Chemistry. 262:14352-14360, 1987.
Prihar G, Fuldner BA, Pcrez-Tur J, Lincoln S, Duff K, Crook R, Hardy J, Phillips CA, Venter C, Talbot C, Clark RB, Goate A, Li J, Potter H, Karran E, Roberts GW, Hutton M, Adams MD. Structure and alternative splicing of the presenilin- 2 gene. Neuroreport. 7:1680-1684, 1996.
Prince JA, Feuk L, Sawyer SL, Gottfries J, Ricksten A, Nagga K, Bogdanovic N, Blennow K, Brookes AJ. Lack of replication of association findings in complex disease: an analysis of 15 polymorphisms in prior candidate genes for sporadic Alzheimer's disease. European Journal of Human Genetics. 9:437-44, 2001.
Podlisny MB, Tolan D, Selkoe DJ. Homology of the amyloid beta protein precursor in monkey and human supports a primate model for beta amyloidosis in Alzheimer's disease. American Journal of Pathology. 138:1423-1435, 1991.
Ponte P, Gonzalez-DeWhitt P, Schiillng J, Miller J, Hsu D, Greenberg B, Davis K, Wallace W, Lieberburg I, Fuller F. A new A4 amyloid mRNA contains a domain homologous to serine protease inhibitors. Nature. 331:525-527, 1988.
Pulliam JF, Jennings CD, Kryscio RJ, Davis DG, Wilson D, Montine TJ, Schmitt FA Markesbery WR. Association of HFE mutations with neurodegeneration and oxidative stress in Alzheimer’s disease and correlation with APOE. American Journal of Medical Genetics. 119B:48–53, 2003.
Rebeck GW, Reiter JS, Strickland DK, Hyman PT. Apolipoprotein F in sporadic Alzheimer's disease: allelic variation and receptor interactions. Neuron. 11:575-580, 1993.
Rebeck GW, Harr SD, Strickland DK, Hyman BT. Multiple, diverse senile plaque-associated proteins are ligands of an apolipoprotein E recep- tor, the alpha 2-macroglobulin receptor/lowdensity- lipoprotein receptor-related protein. Annals of Neurology. 37:211-7, 1995.
Renovize EB. An HLA and family study of Alzhimer’s disease. Psychological Medicine. 14:515-520, 1984.
Reue KL, Quon DH, O'Donnell KA, Dizikes GJ, Fareed GC, Lusis AJ. Cloning and regulation of messenger RNA for mouse Apolipoprotein E. Journal of Biological Chemistry. 259:2100-2107, 1984.
Riazanskaia N, Lukiw W, Grigorenco A, Korovaitseva G, Dvoryanchikov G, Moliaka Y, Nicolaou M,. Farrer L, Bazan NG, Rogaev E. Regulatory region variability in the human presenilin-2 (PSEN2) gene: potential contribution to the gene activity and risk for AD, Molecular Psychiatry. 7:891–898, 2002.
Richey PI, Siedlak SI, Smith MA, Perry G. Apolipoprotein E interaction with the neurofibrillary tangles and senile plaques in Alzheimer disease: implications for disease pathogenesis. Biochemical And Biophysical Research Communications. 208:657-663, 1995.
Robakis NK, Ramakrishna N, Wolfe G, Wisniewski HM. Molecular cloning and characterization of a cDNA encoding the cerebrovascular and neuritic plaque amyloid peptides. Proceeding of National Academy of Sciences USA. 84:4190-4194, 1987.
Rogaev E, Lukiw WI, Vaula G, Haines EL, Rogaeva FA, Tsuda T, Alexandrova N, Liang Y, Mortilla M, Amaducci L. Analysis of the cfos gene on chromosome 14 and the promoter of the amyloid precursor protein gene in familial Alsheimer's disease. Neurology. 43:2275-2279, 1993.
Rooke K, Goate A, Fidani L, Mullan M, Roques P, Rossor M, Hardy J, Charuer-Harlin M.C. Screening of the promoter and the β-amyloid sequence of the APP gene for polymorphisms in families with late onset Alzheimer's disease. Neurodegeneration. 1:237-240, 1992.
Rosen DR, Martin-Morris L, Luo L, White K. A Drosophila gene encoding a protein resembling the human beta-amyloid precursor protein. Proceeding of National Academy of Sciences USA. 86:2478-2482, 1989.
Rossor MN, Fox NC, Beck J, Campbell TC, Collinge J. Incomplete penetrance of familial Alzheimer's disease in a pedigree with a novel presenilin 1 gene mutation. Lancet. 347:1560, 1996.
Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerrière A, Vital A, Dumanchin C, Feuillette S, Brice A, Vercelletto M, Dubas F, Frebourg T, Campion D. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nature Genetics. 38 (1): 11-2, 2006.
Rumble B, Retallack R, Hilbich C, Simms G, Multhaup G, Martins R, Hockey A, Montgomery P, Beyreuther K, Masters CL. Amyloid A4 protein and its precursor in Down's syndrome and Alzheimer's disease. New England Journal of Medicine. 320:1446-1452, 1989.
Sahara N, Yahagi Y, Takagi H, Kondo T, Okochi M, Usami M, Shirasawa T, Mori H. Identification and characterization of presenilin I-467, I- 463 and I-374. FEBS Letters. 381:7-11, 1996.
Saitoh T, Sundsmo M, Roch JM, Kumura N, Cole G, Schubert D, Oltersdorf T, Schenk DB. Secreted form of amyloid-β protein precursor is involved in the growth regulation of fibroblasts. Cell. 58:615-622, 1989.
Salbaum JM, Lemaire HG, Weidemann A, Masters CL, Beyreuther K. The promoter of Alzheimer's disease amyloid A4 precursor gene. EMBO Journal. 7:2807-2813, 1988.
Sanan DA, Weisgraber KH, Russell SJ, Mahley RW, Huang D, Saunders A, Schmechel D, Wisniewski T, Frangione B, Roses AD. Apolipoprotein B associates with beta amyloid peptide of Alzheimer's disease to form novel monofibrils. Isoform apoE4 associates more efficiently than apoE3. Journal of Clinical Investigations. 94:860-869, 1994.
Sandbrink R, Masters, CL, Beyreuther K. Beta-A4- amyloid protein-precursor messenger RNA isoforms without exon-15 are ubiquitously expressed in rat tissues, including brain, but not in neurons. Journal of Biological Chemistry. 269:1510-1517, 1994.
Saunders AM, Strittmatter WJ, Schmechel D, St. George-Hyslop PH, Pericak-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-MacLachlan DR, Alberts MJ, Hulette C, Crain B, Goldgaber D, Roses AD. Association of apolipoprotein E allele E4 with late-onset familial and sporadic Alzheimer's disease. Neurology. 43:1467-1472,1993.
de Sauvage F, Kruys V, Marinx O, Huez G, Octave JN. Alternative polyadenylation of the amyloid protein precursor mRNA regulates translation. EMBO Journal. 11:3099-3103, 1992.
Selkoe DJ, Podlisny MB, Joachim CL, Vickers EA, Lee G, Fritz LC, Oltersdorf T. Betaamyloid precursor protein of Alzheimer disease occurs as 110-135 kilodalton membraneassociated proteins in neural and nonneural tissues. Proceeding of National Academy of Sciences USA. 85:7341-7345, 1988.
Sherrington R, Froelich S, Sotbi S, Campion D, Chi H, Rogaeva BA, Levesque G, Rogaev EI, Lin, C, Liang Y, Ikeda M, Mar L, Brice A, Agid Y, Percy MB, Clerget-Darpoux F, Piacentini S, Marcon G, Nacmias B, Amaducci L, Frebourg I, Lannfelt L, Rommens JM, St George-Hyslop PH. Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant. Human Molecular Genetics. 5:985-988, 1996.
Sinckland DK, Ashcom JD, Williams S, Burgess WH, Migliorini M, Argraves WS. Sequence identity between the α2-macroglobulin receptor and low density lipoprotein receptorrelated protein suggests that this molecule is a multifunctional receptor. Journal of Biological Chemistry. 265:17401-17404, 1990.
Slunt HH, Thinakaran G, Von Koch C, Lo AC, Tanzi RE, Sisodia SS. Expression of a ubiquitous, cross-reactive homologue of the mouse beta-amyloid precursor protein (APP). Journal Biolological Chemistry. 269:2637-2644, 1994.
Small DH, Nurcombe V, Moir R, Michaelson S, Monad D, Beyreuther K, Masters CL. Association and release of amyloid protein precursor of Alzheimer's disease from chick brain extracellular matrix. Journal of Neurosciences. 12:4143-415, 1992.
Smith MA, Perry G. The pathogenesis of Alzheimer disease: an alternative to the amyloid hypothesis. Journal of Neuropathological Experiments in Neurology. 56:217, 1997.
Sparks DL, Scheff SW, Liu H, Landers T, Danner F, Coyne CM, Hunsaker JC. 3rd., Increased density of senile plaques (SP), but not neurofibrillary tangles (NFT), in non-demented individuals with the apolipoprotein E4 allele: comparison to confirmed Alzheimer's disease patients. Journal of Neurological Sciences. 138:97-104, 1996.
Sprecher CA, Grant FJ, Grimm G, O'Hara PJ, Norris F, Norris K, Foster DC. Molecular cloning of the cDNA for a human amyloid precursor protein homolog: evidence for multigene family. Biochemistry. 32:4481-4486, 1993.
St Clair D, Rennie M, Slorach E, Norrman J, Yates C, Carothers A. Apolipoprotein E epsilon-4 allele is a risk factor for familial and sporadic presenile Alzheimer's disease in both homozygote and heterozygote carriers. Journal of Medical Genetics. 32:642-644, 1995.
Strittmatter WJ, Saunders AM, Schmechel D, Pericak- Vance M, Enghild J, Salvesen GS, Roses AD. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proceedings of National Academy of Sciences USA. 90:1977-1981, 1993.
Strittmatter WJ, Weisgraber KH, Goedert M, Saunders AM, Huang D, Corder EH, Dong LM, Jakes R, Alberts MJ, Gilbert JR. Hypothesis: microtubule instability and paired helical filament formation in the Alzheimer disease brain are related to apolipoprotein E genotype. Experiments in Neurology. 125:163-171, 1994.
Strittmatter WJ, Roses AD. Apolipoprotein E and Alzheimer disease. Proceedings of National Academy of Sciences USA. 92:4725-4727, 1995.
Suzuki N, Cheung TT, Cai XD, Odaka A, Otvos LJr, Eckman C, Golde TE, Younkin S. An increased percentage of long amyloid β protein secreted by familial amyloid β protein precursor (13 APP717) mutants. Science. 264:1336-1340,1994.
Takahashi S, Kawarabayasi Y, Nakai T, Sakai J, Yamamoto T. Rabbit very low density lipoprotein receptor: a low density lipoprotein receptor- like protein with distant ligand specificity. Proceedings of National Academy of Sciences USA. 89:9252-9256, 1992.
Takahashi H, Murayama M, Takashima A, Mercken M, Nakazato Y, Noguchi K, Imahori K. Molecular cloning and expression of the rat homologue of presenilin- 1. Neuroscience Letters. 206:113-116, 1996.
Tanahashi H, Kawakatsu S, Kaneko M, Yamanaka H, Takahashi K, Tabira T. Sequence analysis of presenilin-1 gene mutation in Japanese Alzheimer's disease patient. Neuroscience Letters. 218:139-141, 1996.
Tanzi RE, Gusella JF, Watkins PC, Bruns GA, St George-Hyslop P, Van Keuren ML, Patterson D, Pagan S, Kurnit DM, Neve RL. Amyloid β protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science. 235:880-884, 1987.
Tanzi RE, McClatchey M, Lamperti ED, Villa- Komaroff L, Gusella JF, Neve RL. Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer's disease. Nature. 331:528-530, 1988.
Taylor AE, Yip A, Brayne C, Easton D, Evans JG, Xuereb J, Cairns N, Esiri MM, Rubinsztein DC. Genetic association of an LBP- 1c/CP2/LSF gene polymorphism with late onset Alzheimer's disease. Journal of Medical Genetics. 38:232-3, 2001.
Theuns J, Del-Favero J, Dermaut B, Van Duijn CM, Backhovens H, Van den Broeck MV, Serneels S, Corsmit E, Van Broeckhoven CV, Cruts M. Genetic variability in the regulatory region of presenilin 1 associated with risk for Alzheimer’s disease and variable expression. Human Molecular Genetics. 9:325–331, 2000.
Theuns J, Brouwers N, Engelborghs S, Sleegers K, Bogaerts V, Corsmit E, De Pooter T, van Duijn CM, De Deyn PP, Van Broeckhoven C. Promoter mutations that increase amyloid precursor-protein expression are associated with Alzheimer disease. American Journal of Human Genetics. 78 (6): 936-46, 2006.
Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, Kim G, Ratovitsky T, Davenport F, Nordstedt C, Seeger M, Hardy J, Levey AI, Gandy SE, Jenkins NA, Copeland NG, Price DL, Sisodia SS. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron. 17:181-90, 1996.
Thinakaran G, Harris CL, Ratovitski T, Davenport F, Slunt HH, Price DL, Borchelt DR, Sisodia SS. Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. Journal of Biological Chemistry. 272:28415-22, 1997.
Togashi H, Abe K, Mizoguchi A, Takaoka K, Chisaka O, Takeichi M. Cadherin regulates dendritic spine morphogenesis. Neuron. 35:77–89, 2002.
de la Torre JC, Fortin T. A chronic physiological rat model of dementia. Behavioural Brain Research. 63:35-40, 1994.
de la Torre JC. Hemodynamic consequences of deformed microvessels in the brain in Alzheimer's disease. Annals of New York Academy of Sciences. 826:75-91, 1997a.
de la Torre JC. Cerebromicrovascular pathology in Alzheimer's disease compared to normal aging. Gerontology. 43:26-43, 1997b.
de la Torre JC. Critically attained threshold of cerebral hypoperfusion: the CATCH hypothesis of Alzheimer's pathogenesis. Neurobiology of Aging. 21:331-42, 2000.
Town T, Paris D, Fallin D, Duara R, Barker W, Gold M, Crawford F, Mullan M. The 49 lAir apolipoprotein F promoter poly-morphism association with Alzheimer's disease: independent risk and linkage disequilibrium with the known APOF polymorphism. Neuroscience Letters. 252:95-98, 1998.
Van Broeckhoven C, Backhovens H, Cruts M, De Winter G, Bruyland M, Cras P, Martin JJ. Mapping of a gene predisposing to early-onset Alzheimer's disease to chromosome 14q24.3. Nature Genetics. 2:335-339, 1992.
Van Broeckhoven C, Backhovens H, Cruts M, Martin JJ, Crook R, Houlden H, Hardy J. APOE genotype does not modulate age of onset in families with chromosome 14 encoded Alzheimer's disease. Neuroscience Letters. 169:179-180, 1994.
Van Broeckhoven C. Molecular Genetics of Alzheimer disease: Identification of genes and gene mutations. European Journal of Neurology. 35:8-19, 1995.
Van Duijn CM. Epidemiology of the dementias: recent developments and new approaches. Journal of Neurology Neurosurgery and Psychiatry. 60:478-488, 1996.
Van Duijn CM, Cruts M, Theuns J, Van Gassen G, Backhovens H, Van den Broeck M, Wehnert A, Semeels S, Hofman A, Van Broeckhoven C. Genetic association of the presenilin-I regulatory region with early-onset Alzheimer's disease in a population based sample. European Journal of Human Genetics. 7:801-806, 1999.
Van Gassen G, Annaert W, Van Broeckhoven C. Binding partners of Alzheimer's disease proteins: are they physiologically relevant? Neurobiology of Disease. 7:135-51, 2000.
Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Dents P, Taplow DB, Ross S, Amaranta P, Loeloff R, Luo Y, Fisher S, et al. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 286:735-741,1999.
Villa A, Latasa MJ, Pascual A. Nerve growth factor modulates the expression and secretion of beta-amyloid precursor protein through different mechanisms in PC12 cells. Journal of Neurochemistry. 77:1077-84, 2001.
Walter J, Capell A, Grunberg J, Pesold B, Schindzielorz A, Prior R, Podlisny MB, Fraser P, Hyslop PS, Selkoe DJ, Haass C. The Alzheimer's disease-associated presenilins are differentially phosphorylated proteins located predominantly within the endoplasmic reticulum. Molecular Medicine. 2:673-691, 1996.
Wang X, Gruenstein EI. Mechanism of synchronized Ca2+ oscillations in cortical neurons. Brain Research. 767:239-249, 1997.
Wang X, Luebbe P, Gruenstein E, Zemlan F. Apolipoprotein E (ApoE) peptide regulates tau phosphorylation via two different signaling pathways. Journal of Neuroscience Research. 51:658-65, 1998.
Wang X, Luedecking EK, Minster RL, Ganguli M, DeKosky ST, Kamboh MI. Lack of association between the α2-macroglobulin polyorphisms and Alzheimer’s disease. Human Genetics. 108:105-108, 2001.
Wasco W, Bupp K, Magendantz M, Gusella JF, Tanzi RE, Solomon F. Identification of a mouse brain cDNA that encodes a protein related to the Alzheimer disease-associated amyloid beta-protein precursor. Proceeding of National Academy of Sciences USA. 89:10758-10762, 1992.
Wasco W, Gurubhagavatula S, Paraffis MD, Romano D, Sisodia SS, Hyman BT, Neve RL, Tanzi RE. Isolation and characterization of the human APLP2 gene encoding a homologue of the Alzheimer's associated amyloid 13 protein precursor. Nature Genetics. 5:95-100,1993.
Wavrant-DeVrieze F, Lambert JC, Stas L, Crook R, Cottel D, Pasquier F, Frigard B, Lambrechts M, Thiry E, Amouyel P, Tur JP, Chartier- Harlin MC, Hardy J, Van Leuven F. Association between coding variability in the LRP gene and the risk of late-onset Alzheimer's disease. Human Genetics. 104:432-4,1999.
Wavrant-De Vrieze F, Crook R, Holmans P, Kehoe P, Owen MJ, Williams J, Roehl K, Laliiri DK, Shears S, Booth J, Wu W, Goate A, Chartier-Harlin MC, Hardy J, Perez-Tur J. Genetic variability at the amyloid-β precursor protein locus may contribute to the risk of lateonset Alzheimer's disease. Neuroscience Letters. 269:67-70, 1999.
Weidemann A, Konig G, Bunke D, Fischer P, Salbaum JM, Masters CL, Beyreuther K. Identification, biogenesis and localization of precursors of Alzheimer's disease A4 amyloid protein. Cell. 57:115-126, 1989.
Wisniewski T, Frangione B. Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neuroscience Letters. 135:235-238, 1992.
Wragg M, Hutton M, Talbot C, Busfield F, Han SW, Lendon C, Clark RB, Morris JC, Edwards D, Goate A, Pfeiffer F, Crook R, Prihar G, Philips H, Baker M, Hardy J, Rossor M, Houlden H, Karran B, Roberts G, Craddock N. Genetic association between intronic polymorphism in presenilin-l gene and late-onsetAlzheimer's disease. Lancet. 347:509-512, 1996.
Xia X, Wang P, Sun X, Soriano S, Shum WK, Yamaguchi H, Trumbauer ME, Takashima A, Koo EH, Zheng H. The aspartate-257 of presenilin 1 is indispensable for mouse development and production of β-amyloid peptides through β-cateninindependent mechanisms. Proceedings of National Academy of Sciences USA. 99:8760–5, 2002.
Yang DS, Smith JD, Zhou Z, Gandy SE, Martins RN. Characterization of the binding of amyloidbeta peptide to cell culture-derived native apolipoprotein ε2, ε3, and ε4 isoforms and to isoforms from human plasma. Journal of Neurochemistry. 68:721-725, 1997.
Yoo AS, Cheng I, Chung S, Grenfell TZ, Lee H, Pack-Chung E, Handler M, Shen J, Xia W, Tesco G, Saunders AJ, Ding K, Frosch MP, Tanzi RE, Kim TW. Presenilin-mediated modulation of capacitative calcium entry. Neuron. 27:561–72, 2000.
Zambrano N, Minopoli G, de Candia P, Russo, Tommaso. The Fe65 adaptor protein interacts through its PID1 domain with the transcription factor CP2/LSF/LBP1. Journal of Biological Chemistry. 273:20128-20133, 1998.
Zhang Z, Drzewiecki GJ, May YC, Rydel RE, Paul SM, HyslopYA. Inhibition of alpha 2- macroglobulin/proteinase-mediated degradation of amyloid beta peptide by apolipoprotein E and alpha I -antichymotrypsin. International Journal of Experimental Clinical Investigations. 3:156-161, 1996.
Zheng H, Jiang M, Trumbauer ME, Sirinathsinghji DJ, Hopkins R, Smith DW, Heavens RP, Dawson GR, Boyce S, Conner MW. beta- Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell. 81:525-531, 1995.
Zubenko GS, Hughes HB, Stiffler JS, Hurtt MR, Kaplan BB. A genome survey for novel Alzheimer disease risk loci: results at 10-cM resolution. Genomics. 50:121–8, 1998.