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

被引:1269
作者
Jankowsky, JL
Fadale, DJ
Anderson, J
Xu, GM
Gonzales, V
Jenkins, NA
Copeland, NG
Lee, MK
Younkin, LH
Wagner, SL
Younkin, SG
Borchelt, DR
机构
[1] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA
[2] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA
[3] Mayo Clin Jacksonville, Jacksonville, FL 32224 USA
[4] Merck Res Labs, La Jolla, CA 92037 USA
[5] NCI, Mouse Canc Genet Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA
[6] Neurogenet Inc, La Jolla, CA 92037 USA
关键词
D O I
10.1093/hmg/ddh019
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Amyloid precursor protein (APP) is endoproteolytically processed by BACE1 and gamma-secretase to release amyloid peptides (Abeta40 and 42) that aggregate to form senile plaques in the brains of patients with Alzheimer's disease (AD). The C-terminus of Abeta40/42 is generated by gamma-secretase, whose activity is dependent upon presenilin (PS 1 or 2). Missense mutations in PS1 (and PS2) occur in patients with early-onset familial AD (FAD), and previous studies in transgenic mice and cultured cell models demonstrated that FAD-PS1 variants shift the ratio of Abeta40 : 42 to favor Abeta42. One hypothesis to explain this outcome is that mutant PS alters the specificity of gamma-secretase to favor production of Abeta42 at the expense of Abeta40. To test this hypothesis in vivo, we studied Abeta40 and 42 levels in a series of transgenic mice that co-express the Swedish mutation of APP (APPswe) with two FAD-PS1 variants that differentially accelerate amyloid pathology in the brain. We demonstrate a direct correlation between the concentration of Abeta42 and the rate of amyloid deposition. We further show that the shift in Abeta42 : 40 ratios associated with the expression of FAD-PS1 variants is due to a specific elevation in the steady-state levels of Abeta42, while maintaining a constant level of Abeta40. These data suggest that PS1 variants do not simply alter the preferred cleavage site for gamma-secretase, but rather that they have more complex effects on the regulation of gamma-secretase and its access to substrates.
引用
收藏
页码:159 / 170
页数:12
相关论文
共 82 条
[1]   A vector for expressing foreign genes in the brains and hearts of transgenic mice [J].
Borchelt, DR ;
Davis, J ;
Fischer, M ;
Lee, MK ;
Slunt, HH ;
Ratovitsky, T ;
Regard, J ;
Copeland, NG ;
Jenkins, NA ;
Sisodia, SS ;
Price, DL .
GENETIC ANALYSIS-BIOMOLECULAR ENGINEERING, 1996, 13 (06) :159-163
[2]   Accumulation of proteolytic fragments of mutant presenilin 1 and accelerated amyloid deposition are co-regulated in transgenic mice [J].
Borchelt, DR ;
Lee, MK ;
Gonzales, V ;
Slunt, HH ;
Ratovitski, T ;
Jenkins, NA ;
Copeland, NG ;
Price, DL ;
Sisodia, SS .
NEUROBIOLOGY OF AGING, 2002, 23 (02) :171-177
[3]   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
[4]   Familial Alzheimer's disease-linked presenilin 1 variants elevate A beta 1-42/1-40 ratio in vitro and in vivo [J].
Borchelt, DR ;
Thinakaran, G ;
Eckman, CB ;
Lee, MK ;
Davenport, F ;
Ratovitsky, T ;
Prada, CM ;
Kim, G ;
Seekins, S ;
Yager, D ;
Slunt, HH ;
Wang, R ;
Seeger, M ;
Levey, AI ;
Gandy, SE ;
Copeland, NG ;
Jenkins, NA ;
Price, DL ;
Younkin, SG .
NEURON, 1996, 17 (05) :1005-1013
[5]  
BURDICK D, 1992, J BIOL CHEM, V267, P546
[6]   Presenilin-1 regulates intracellular trafficking and cell surface delivery of β-amyloid precursor protein [J].
Cai, DM ;
Leem, JY ;
Greenfield, JP ;
Wang, P ;
Kim, BS ;
Wang, RS ;
Lopes, KO ;
Kim, SH ;
Zheng, H ;
Greengard, P ;
Sisodia, SS ;
Thinakaran, G ;
Xu, HX .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (05) :3446-3454
[7]   RELEASE OF EXCESS AMYLOID BETA-PROTEIN FROM A MUTANT AMYLOID BETA-PROTEIN PRECURSOR [J].
CAI, XD ;
GOLDE, TE ;
YOUNKIN, SG .
SCIENCE, 1993, 259 (5094) :514-516
[8]   Presenilin-1 differentially facilitates endoproteolysis of the β-amyloid precursor protein and Notch [J].
Capell, A ;
Steiner, H ;
Romig, H ;
Keck, S ;
Baader, M ;
Grim, MG ;
Baumeister, R ;
Haass, C .
NATURE CELL BIOLOGY, 2000, 2 (04) :205-211
[9]  
CHENG SN, 2000, P INT WORKSH ANN COM, V1, P275
[10]   Nicastrin is required for Presenilin-mediated transmembrane cleavage in Drosophila [J].
Chung, HM ;
Struhl, G .
NATURE CELL BIOLOGY, 2001, 3 (12) :1129-1132