Mean age of onset in familial Alzheimer's disease is determined by amyloid beta 42

被引：82

作者：

Duering, M

Grimm, MOW

Grimm, HS

Schröder, J

Hartmann, T

机构：

[1] Ctr mOl Biol Heidelberg, D-69120 Heidelberg, Germany

[2] Heidelberg Univ, Sect Gerontopsychiat, Psychiat Clin, D-69115 Heidelberg, Germany

来源：

NEUROBIOLOGY OF AGING | 2005年 / 26卷 / 06期

关键词：

Alzheimer's disease; beta amyloid-protein; presenilin-1; age of onset; pathogenesis;

D O I：

10.1016/j.neurobiolaging.2004.08.002

中图分类号：

R592 [老年病学]; C [社会科学总论];

学科分类号：

03 ; 0303 ; 100203 ;

摘要：

More than 130 known mutations in the presenilin-1 (PS1) gene result in familial Alzheimer's disease (FAD) with a mutation specific age of disease onset. These mutations increase amyloid beta 42 (A beta 42) levels, and this increase has been validated in recent years as one pathogenic factor in FAD. However, further malfunctions of mutant presenilin-1 are discussed as well. In order to assess the weight of A beta 42 regarding the pathogenesis of FAD, we expressed mutant forms of PS1 (30-65 years onset age) in COS-7 cells and analyzed amyloid beta levels by a novel ELISA. We found a strong correlation (r = 0.98; p < 0.00 1) between the A beta 40/42-ratio and mean age of disease onset indicating a substantial extent of A beta 42 contribution to FAD pathology. Our data strongly suggest that A beta 42 is the decisive factor for age of onset in FAD. (c) 2004 Elsevier Inc. All rights reserved.

引用

收藏

页码：785 / 788

页数：4

相关论文

共 19 条

[1] Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins [J].

Borchelt, DR ;

Ratovitski, T ;

vanLare, J ;

Lee, MK ;

Gonzales, V ;

Jenkins, NA ;

Copeland, NG ;

Price, DL ;

Sisodia, SS .

NEURON, 1997, 19 (04) :939-945

[2] GENE DOSE OF APOLIPOPROTEIN-E TYPE-4 ALLELE AND THE RISK OF ALZHEIMERS-DISEASE IN LATE-ONSET FAMILIES [J].

CORDER, EH ;

SAUNDERS, AM ;

STRITTMATTER, WJ ;

SCHMECHEL, DE ;

GASKELL, PC ;

SMALL, GW ;

ROSES, AD ;

HAINES, JL ;

PERICAKVANCE, MA .

SCIENCE, 1993, 261 (5123) :921-923

[3] The over-expression of the wild type or mutant forms of the presinilin-1 protein alters glycoprotein processing in a human neuroblastoma cell line [J].

Farquhar, MJ ;

Gray, CW ;

Breen, KC .

NEUROSCIENCE LETTERS, 2003, 346 (1-2) :53-56

[4] γ-secretase cleavage site specificity differs for intracellular and secretory amyloid β [J].

Grimm, HS ;

Beher, D ;

Lichtenthaler, SF ;

Shearman, MS ;

Beyreuther, K ;

Hartmann, T .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (15) :13077-13085

[5] Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice [J].

Guo, Q ;

Fu, WM ;

Sopher, BL ;

Miller, MW ;

Ware, CB ;

Martin, GM ;

Mattson, MP .

NATURE MEDICINE, 1999, 5 (01) :101-106

[6] Alzheimer's PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid beta-peptide [J].

Guo, Q ;

Furukawa, K ;

Sopher, BL ;

Pham, DG ;

Xie, J ;

Robinson, N ;

Martin, GM ;

MAttson, MP .

NEUROREPORT, 1996, 8 (01) :379-383

[7] Mortality with dementia: Results from a French prospective community-based cohort [J].

Helmer, C ;

Joly, P ;

Letenneur, L ;

Commenges, D ;

Dartigues, JF .

AMERICAN JOURNAL OF EPIDEMIOLOGY, 2001, 154 (07) :642-648

[8] Capacitive calcium entry is directly attenuated by mutant presenilin-1, independent of the expression of the amyloid precursor protein [J].

Herms, J ;

Schneider, I ;

Dewachter, I ;

Caluwaerts, N ;

Kretzschmar, H ;

Van Leuven, F .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (04) :2484-2489

[9] Analysis of heterogeneous beta A4 peptides in human cerebrospinal fluid and blood by a newly developed sensitive Western blot assay [J].

Ida, N ;

Hartmann, T ;

Pantel, J ;

Schroder, J ;

Zerfass, R ;

Forstl, H ;

Sandbrink, R ;

Masters, CL ;

Beyreuther, K .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (37) :22908-22914

[10] Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo:: evidence for augmentation of a 42-specific γ secretase [J].

Jankowsky, JL ;

Fadale, DJ ;

Anderson, J ;

Xu, GM ;

Gonzales, V ;

Jenkins, NA ;

Copeland, NG ;

Lee, MK ;

Younkin, LH ;

Wagner, SL ;

Younkin, SG ;

Borchelt, DR .

HUMAN MOLECULAR GENETICS, 2004, 13 (02) :159-170