PATOLOGÍA MOLECULAR DEL ALZHEIMER
cling as detected by labeled monoclonal antibody. J Cell Sci 1996; 109: 991-8. 9. Van-Nostrand WE, Farrow JS, Wagner SL, Bhasin R, Goldgaber D, Cotman CW, Cunningham DD. The predominant form of the amyloid β-protein precursor in human brain is protease nexin II. Proc Natl Acad Sci USA 1991; 88: 10302-6. 10. Yamazaki T, Koo EH, Selkoe DJ. Trafficking of cell-surface amyloidbeta protein precursor. II. Endocytosis, recycling and lysosomal targeting detected by immunolocalization. J Cell Sci 1996; 109: 999-1008. 11. Seubert P, Vigo-Pelfrey C, Esch F, Lee M, Dovey H, Davis D. Isolation and quantification of soluble Alzheimer’s β-peptide from biological fluids. Nature 1992; 359: 325-7. 12. Vigo-Pelfrey C, Kuo YM, Coria F, Roher A. Familial Alzheimer’s disease, amyloid beta pathology and neuroprotective strategies. Neurologia 1996; 11 (Suppl 3): S87-92. 13. Vigo-Pelfrey C, Lee D, Keim P, Lieberburg I, Schenk DB. Characterization of β-amyloid peptides from normal cerebral spinal fluid. J Neurochem 1994; 61: 1965-8. 14. Ghersi-Egea JF, Gorevic PD, Ghiso J, Frangione B, Patlak CS, Fenstermacher JD. Fate of cerebrospinal fluid-borne amyloid beta peptide: rapid clearance into blood and appreciable accumulation by cerebral arteries. J Neurochem 1996; 67: 880-3. 15. Tischer E, Cordell B. Beta-amyloid precursor. Location of transmembrane domain and specificity of gamma-secretase cleavage. J Biol Chem 1996; 271: 21914-9. 16. Lammich S, Kojro E, Postina R, Gilbert S, Pfeiffer R, Jasionowski M, et al. Constitutive and regulated α-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Proc Natl Acad Sci USA 1999; 96: 3922-7. 17. Yan R, Blenkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, et al. Membrane-anchored aspartyl protease with Alzheimer’s disease beta-secretase activity. Nature 1999; 402: 533-7. 18. López-Pérez E, Zhang Y, Frank SJ, Creemers J, Seidah N, Checler F. Constitutive alpha-secretase cleavage of the beta-amyloid precursor protein in the furin-deficient LoVo cell line: involvement of the prohormone convertase 7 and the disintegrin metalloprotease ADAM 10. J Neurochem 2001; 76: 1532-9. 19. Skovronsky DM, Moore DB, Milla ME, Doms RW, Lee VM-Y. Protein kinase C-dependent α-secretase competes with β-secretase for cleavage of amyloid-β precursor protein in the trans-Golgi network. J Biol Chem 2000; 275: 2568-75. 20. Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, et al. Purification and cloning of amyloid precursor protein β-secretase from human brain. Nature 1999; 402: 537-40. 21. Vasaar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, et al. β-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999; 286: 735-41. 22. Bennett BD, Denis P, Haniu M, Teplow DB, Kahn S, Louis KS, et al. A furin-like convertase mediates pro-peptide cleavage of BACE, the Alzheimer’s β-secretase. J Biol Chem 2000; 275: 37712-7. 23. Farzan M, Schnitzler CE, Vasilieva N, Leung D, Choe H. BACE2; a βsecretase homolog, cleaves at the β site and within the amyloid-β region of the amyloid-β precursor protein. Proc Natl Acad Sci USA 2000; 97: 9712-7. 24. Czech C, Tremp G, Pradier L. Presenilins and Alzheimer’s disease: bio-
logical functions and pathogenic mechanisms. Prog Neurobiol 2000; 60: 363-84. 25. Kosik KS, Joachim CL, Selkoe DJ. Microtubule-associated protein τ (tau) is a major antigenic component of paired helical filaments. Proc Natl Acad Sci USA 1986; 83: 4044-8. 26. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorilation of the microtubule-associated protein τ (tau) in Alzheimer’s cytoskeletal pathology. Proc Natl Acad Sci USA 1986; 83: 4913-7. 27. Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR. Tau isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 2000; 33: 95-130. 28. Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara I. Visualization of Aβ42(43) and Aβ40 in senile plaques with end-specific monoclonals: evidence that an initially deposited species is Aβ42(43). Neuron 1994; 13: 45-52. 29. Roher A, Lowenson J, Clarke S, Woods AS, Cotter RJ, Gowing E, et al. Structural alterations of the peptide backbone of β-amyloid core protein may account for its deposition and stability in Alzheimer’s disease. J Biol Chem 1993; 268: 3072-83. 30. Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-Tur J. Increased amyloid-β42/43 in brains of mice expressing mutant presenilin 1. Nature 1996; 383: 710-3. 31. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD. Apolipoprotein E: high avidity binding to βamyloid and increased frequency of type 4 allele in late-onset familial Alzheimer’s disease. Proc Natl Acad Sci USA 1993; 90: 1977-81. 32. Sanan DA, Weisgraber KH, Russell SJ, Mahley RW, Huang D, Saunders A, et al. Apolipoprotein E associates with β amyloid peptide of Alzheimer’s disease to form novel monofibrils. Isoform apoE4 associates more efficiently than apoE3. J Clin Invest 1994; 94: 860-9. 33. Yan SD, Chen X, Fu J, Chen M, Zhu H, et al. RAGE and amyloid-β peptide neurotoxicity in Alzheimer’s disease. Nature 1996; 382: 685-91. 34. Bush AI, Pettingell WH, Multhaup G, d Paradis M, Vonsattel JP, Gusella JF, et al. Rapid induction of Alzheimer Aβ amyloid by zinc. Science 1994; 91: 1416-20. 35. Ma J, Yee A, Brewer HB Jr, Das S, Potter H. Amyloid-associated proteins α1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer β-protein into filaments. Nature 1994; 372: 92-9. 36. Coria F, Castano E, Prelli F, Larrondo-Lillo M, Van Duinen S, Shelanski ML, et al. Isolation and characterization of amyloid P component from Alzheimer’s diseases and other types of cerebral amyloidosis. Lab Invest 1988; 58: 454-8. 37. Snow AD, Kinsella MG, Parks E, Sekiguchi RT, Miller JD, Kimata K, et al. Differential binding of vascular cell-derived proteoglycans (perlecan, biglycan, decorin, and versican) to the beta-amyloid protein of Alzheimer’s disease. Arch Biochem Biophys 1995; 320: 84-95. 38. Liu F, Iqbal K, Grundke-Iqbal I, Hart GW, Gong CX. O-GlcNAcylation regulates phosphorylation of tau: A mechanism involved in Alzheimer's disease. Proc Natl Acad Sci USA 2004; 101: 10804-9. 39. Coria F, Moreno A, Rubio I, Garcia MA, Morato E, Mayor F Jr. The cellular pathology associated with β-amyloid deposits in non-demented elderly individuals. Neuropathol Appl Neurobiol 1993; 19: 261-8. 40. Mattson MP, Rydel RE. Amyloid ox-tox transducers. Nature 1996; 382: 674-5.
AVANCES EN LA PATOLOGÍA MOLECULAR DE LA ENFERMEDAD DE ALZHEIMER Resumen. Introducción. La enfermedad de Alzheimer (EA) es el resultado de la acumulación progresiva de una proteína específica (proteína beta) en el parénquima cerebral, en forma de depósitos amiloides. Desarrollo. Los depósitos amiloides en la EA son el resultado de factores genéticos y ambientales que alteran el metabolismo de la proteína precursora del amiloide beta. La acumulación de amiloide en el tejido cerebral desencadena fenómenos tóxicos que se traducen en pérdida sináptica y, más tarde, en la formación de ovillos neurofibrilares y muerte neuronal. Conclusiones. La pérdida sináptica se correlaciona con los trastornos de memoria característicos de las primeras fases de la enfermedad, y la pérdida neuronal, con la demencia en fases más avanzadas. Esta sucesión de hechos, conocida como ‘cascada amiloide’, se apoya en múltiples estudios genéticos y experimentales. [REV NEUROL 2006; 42: 306-9] Palabras clave. Amiloide beta. Amiloidosis. Enfermedad de Alzheimer. Ovillos neurofibrilares. Proteína tau.
EVOLUÇÃO NA PATOLOGIA MOLECULAR DA DOENÇA DE ALZHEIMER Resumo. Introdução. A doença de Alzheimer (DA) resulta da acumulação progressiva de uma proteína específica (proteína beta) no parênquima cerebral, em forma de depósitos amilóides. Desenvolvimento. Os depósitos amilóides na DA são o resultado de factores genéticos e ambientais que alteram o metabolismo da proteína precursora do amilóide beta. A acumulação de amilóide no tecido cerebral desencadeia fenómenos tóxicos que se traduzem em perda sináptica e, posteriormente, na formação de nódulos neurofibrilhares e morte neuronal. Conclusões. A perda sináptica correlacionase com as alterações de memória características das primeiras fases da doença, e a perda neuronal, com a demência em fases mais avançadas. Esta sucessão de acontecimentos, conhecida como a ‘cascata amilóide’, é apoiada por múltiplos estudos genéticos e experimentais. [REV NEUROL 2006; 42: 306-9] Palavras chave. Amilóide beta. Amiloidose. Doença de Alzheimer. Nódulos neurofibrilhares. Proteína tau.
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