期刊
ACS CHEMICAL NEUROSCIENCE
卷 -, 期 -, 页码 -出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.2c00765
关键词
Alzheimer?s disease; amyloid fl; protein aggregation; lipid membranes; aggregation kinetics; cryo-electron microscopy
资金
- European Research Council [337969]
- BBSRC
- Newman Foundation
- Wellcome Trust
- Cambridge Centre for Misfolding Diseases
- UK Engineering and Physical Sciences Research Council (EPSRC) [EP/S023046/1]
- Fluidic Analytics Ltd.
- EPSRC Underpinning Multi-User Equipment Call [EP/P030467/1]
- European Research Council (ERC) [337969] Funding Source: European Research Council (ERC)
Intracellular Afl42 is primarily produced in the endoplasmic reticulum and Golgi apparatus, where lipid bilayers have been shown to promote the aggregation of Afl. The study demonstrates that the ER and Golgi model membranes inhibit the aggregation of Afl42, suggesting an evolutionary optimization of lipid composition to prevent intracellular Afl aggregation.
The aggregation of the amyloid fl (Afl) peptide is one of the molecular hallmarks of Alzheimer's disease (AD). Although Afl deposits have mostly been observed extracellularly, various studies have also reported the presence of intracellular Afl assemblies. Because these intracellular Afl aggregates might play a role in the onset and progression of AD, it is important to investigate their possible origins at different locations of the cell along the secretory pathway of the amyloid precursor protein, from which Afl is derived by proteolytic cleavage. Senile plaques found in AD are largely composed of the 42-residue form of Afl (Afl42). Intracellularly, Afl42 is produced in the endoplasmatic reticulum (ER) and Golgi apparatus. Since lipid bilayers have been shown to promote the aggregation of Afl, in this study, we measure the effects of the lipid membrane composition on the in vitro aggregation kinetics of Afl42. By using large unilamellar vesicles to model cellular membranes at different locations, including the inner and outer leaflets of the plasma membrane, late endosomes, the ER, and the Golgi apparatus, we show that Afl42 aggregation is inhibited by the ER and Golgi model membranes. These results provide a preliminary map of the possible effects of the membrane composition in different cellular locations on Afl aggregation and suggest the presence of an evolutionary optimization of the lipid composition to prevent the intracellular aggregation of Afl.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据