The APP and PS1/2 Mutations Linked to Early Onset Familial Alzheimer’s Disease Increase the Extracellular Concentration of Aβ1–42(43)
The amyloid β protein (Aβ) is an ~4 kD secreted protein that is derived from a set of large, alternatively spliced precursor proteins collectively referred to as the amyloid β protein precursor (βAPP). Secreted Aβ is readily detected in cerebrospinal fluid (CSF), plasma, and medium conditioned by cultured cells (Seubert et al. 1992; Shoji et al. 1992; Haass et al. 1992; Busciglio et al. 1993). Most secreted Aβ is Aβ1-40, but a small component (5-10%) is Aβ1–42 (Dovey et al. 1993; Vigo-Pelfrey et al. 1993; Suzuki et al. 1994). A large amount of amyloid β protein (Aβ) is deposited extracellularly in the senile plaques that are invariably observed in the brains of patients with all forms of Alzheimer’s disease (AD). Aβ1-42 appears to be particularly important in AD because it forms insoluble amyloid fibrils more rapidly than Aβ1-40 in vitro (Hilbich etal. 1991; Burdick et al. 1992; Jarrett et al. 1993; Jarrett and Lansbury 1993) and is deposited early and selectively in senile plaques (Iwatsubo et al. 1995). Extracellular Aβ deposition could be 1) an essential early event in AD pathogenesis, 2) an “innocent” marker that is invariably associated with some other change that drives AD pathogenesis, or 3) an unimportant, end-stage consequence of AD pathology. To examine the importance of Aβ in AD, we have analyzed the effect of the amyloid β protein (APP; Goate et al. 1991; Mullan et al. 1992), presenilin 1 (PS1; Sherrington et al. 1995) and presenilin 2 (PS2; Levey-Lahad et al. 1995; Rogaev et al. 1995) mutations that are known to cause early onset familial AD (FAD) on extracellular Aβ concentration.
KeywordsCrystallization Fibril Carboxy Mellon Scrapie
Unable to display preview. Download preview PDF.
- Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada C-M, Kim G, Seekins S, Yager D, Slunt HH, Wang R, Seeger M, Levey AI, Gandy SE, Copeland NG, Jenkins NA, Price DL, Younkin SG, Sisodia SS (1996) Familial Alzheimer’s disease-linked presenilin 1 variants elevate A*#x03B2;i-42/1–40 ratio in vitro and in vivo. Neuron 17: 1005–1013PubMedCrossRefGoogle Scholar
- Castano E, Prelli F, Wisniewski T, Golabek A, Kumar RA, Soto C, Frangione B (1995) Fibrillogenesis in Alzheimer’s disease of the amyloid *#x03B2; peptides and apolipoprotein E. Biochem J 306: 599–604Google Scholar
- Citron M, Vigo-Pelfrey C, Teplow DB, Miller C, Schenk D, Johnston J, Winblad B, Venizelos N, Lannfelt L, Selkoe DJ (1994) Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation. Proc Natl Acad Sei USA 91: 11993–11997CrossRefGoogle Scholar
- Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Yao H, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St George Hyslop P, Selkoe DJ (1997) Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid βprotein in both transfected cells and transgenic mice. Nature Med 3: 67–72PubMedCrossRefGoogle Scholar
- Duff K, Eckman C, Zehr C, Yu X, Prada C-M, Perez-Tur J, Hutton M, Buee L, Harigaya Y, Yager D, Morgan D, Gordon MN, Holcomb L, Refolo L, Zenk B, Hardy J, Younkin S (1996) Increased amyloid-*#x03B2;42(43) in brains of mice expressing mutant presenilin 1. Nature 383: 710–713PubMedCrossRefGoogle Scholar
- Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, Mant R, Newton P, Rooke K, Roques P, Talbot C, Pericak-Vance M, Roses A, Williamson R, Rossor M, Owen M, Hardy J (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349: 704–706PubMedCrossRefGoogle Scholar
- Rogaev E, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T, Mar L, Sorbi S, Nacmias B, Piacentini S, Amaducci L, Chumakov I, Cohen D, Lannfelt L, Fraser PE, Rommens JM, St George-Hyslop PH (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: 775–778PubMedCrossRefGoogle Scholar
- Seubert P, Vigo-Pelfrey C, Esch F, Lee M, Dovey H, Davis D, Sinha S, Schlossmacher M, Whaley J, Swindlehurst C, McCormack R, Wolfert R, Selkoe D, Lieberburg I, Schenk D (1992) Isolation and quantification of soluble Alzheimer’s βpeptide from biological fluids. Nature 359: 325–327PubMedCrossRefGoogle Scholar
- Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin J-F, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov Y, Pollen D, Wasco W, Haines JL, Da Silva R, Pericak-Vance M, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH (1995) Cloning of a novel gene bearing missense mutations in early onset familial Alzheimer disease. Nature 375: 754–760PubMedCrossRefGoogle Scholar
- Wisniewski T, Castano EM, Golabek A, Vogel T, Frangione B (1994) Acceleration of Alzheimer’s fibril formation by apolipoprotein E in vitro. Am J Pathol 145: 1030–1035Google Scholar