Interrelationship between Changes in the Amyloid β 42/40 Ratio and Presenilin 1 Conformation

被引:0
作者
Katarzyna Marta Zoltowska
Masato Maesako
Oksana Berezovska
机构
[1] MassGeneral Institute for Neurodegenerative Disease,Department of Neurology
[2] Massachusetts General Hospital,undefined
[3] Harvard Medical School,undefined
来源
Molecular Medicine | 2016年 / 22卷
关键词
Presenilin (PS1); Fluorescence Lifetime Imaging Microscopy; Pathogenic Shift; Reciprocal Cross-talk; Amyloid Pathology;
D O I
暂无
中图分类号
学科分类号
摘要
The ratio of the longer (Aβ42/Aβ43) to shorter (Aβ40) species is a critical factor determining amyloid fibril formation, neurotoxicity and progression of the amyloid pathology in Alzheimer’s disease. The relative levels of the different Aβ species are affected by activity and conformation of the γ-secretase complex catalytic component presenilin 1 (PS1). The enzyme exists in a dynamic equilibrium of the conformational states, with so-called “close” conformation associated with the shift of the γ-secretase cleavage toward the production of longer, neurotoxic Aβ species. In the current study, fluorescence lifetime imaging microscopy, spectral Förster resonance energy transfer, calcium imaging and cytotoxicity assays were utilized to explore a reciprocal link between the Aβ42 and Aβ40 peptides present at various ratios and PS1 conformation in primary neurons. We report that exposure to Aβ peptides at a relatively high ratio of Aβ42/40 causes conformational change within the PS1 subdomain architecture toward the pathogenic “closed” state. Mechanistically, the Aβ42/40 peptides present at the relatively high ratio increase intracellular calcium levels, which were shown to trigger pathogenic PS1 conformation. This indicates that there is a reciprocal cross-talk between the extracellular Aβ peptides and PS1 conformation within a neuron, with Aβ40 showing some protective effect. The pathogenic shift within the PS1 domain architecture may further shift the production of Aβ peptides toward the longer, neurotoxic Aβ species. These findings link elevated calcium, Aβ42 and PS1/γ-secretase conformation, and offer possible mechanistic explanation of the impending exacerbation of the amyloid pathology.
引用
收藏
页码:329 / 337
页数:8
相关论文
共 67 条
[1]  
Hardy J(2002)The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics Science 297 353-6
[2]  
Selkoe DJ(1989)Alzheimer’s disease: mismatch between amyloid plaques and neuritic plaques Neurosci. Lett. 103 24-28
[3]  
Braak H(2009)gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment J. Neurosci. 29 13042-52
[4]  
Braak E(2013)C-terminal turn stability determines assembly differences between Abeta40 and Abeta42 J. Mol. Biol. 425 292-308
[5]  
Ohm T(2014)gamma-Secretase processing and effects of gamma-secretase inhibitors and modulators on long Abeta peptides in cells J. Biol. Chem. 289 3276-87
[6]  
Bohl J(2006)Distinct early folding and aggregation properties of Alzheimer amyloid-beta peptides Abeta40 and Abeta42: stable trimer or tetramer formation by Abeta42 J. Biol. Chem. 281 24414-22
[7]  
Takami M(1999)Neurotoxicity and oxidative damage of beta amyloid 1–42 versus beta amyloid 1–40 in the mouse cerebral cortex Ann. N. Y. Acad. Sci. 893 314-20
[8]  
Roychaudhuri R(2014)Alzheimer presenilin-1 mutations dramatically reduce trimming of long amyloid beta-peptides (Abeta) by gamma-secretase to increase 42-to-40-residue Abeta J. Biol. Chem. 289 31043-52
[9]  
Ran Y(2010)Neurotoxicity of Alzheimer’s disease Abeta peptides is induced by small changes in the Abeta42 to Abeta40 ratio EMBO J. 29 3408-20
[10]  
Chen YR(2008)The ratio of monomeric to aggregated forms of Abeta40 and Abeta42 is an important determinant of amyloid-beta aggregation, fibrillogenesis, and toxicity J. Biol. Chem. 283 28176-89