Low-Density Lipoprotein Receptor-Related Protein 6 Cell Surface Availability Regulates Fuel Metabolism in Astrocytes.
Low-Density Lipoprotein Receptor-Related Protein 6 Cell Surface Availability Regulates Fuel Metabolism in Astrocytes.
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DOI：
10.1002/advs.202004993
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Kwan KM
中科院分区：
文献类型：
--
作者：
Chow HM;Sun JK;Hart RP;Cheng KK;Hung CHL;Lau TM;Kwan KM
星形胶质细胞能量代谢的早期变化与迟发性阿尔茨海默病（LOAD）有关，但其潜在机制仍然难以捉摸。先前的研究表明LRP 6基因中的同义SNP（rs 1012672，C→T）与LOAD之间存在关联;这确实与额叶皮层区域LRP 6基因表达减少相关。作者表明，LRP 6是星形胶质细胞上独特的Wnt辅助受体，作为调节其代谢景观的双峰开关。Wnt‐ LRP 6介导的mTOR‐AKT轴对于维持葡萄糖代谢至关重要。在其缺失的情况下，Wnt开关激活LRP 6-非依赖性Ca 2 +-PKC-NFAT轴，导致有利于谷氨酰胺和支链氨基酸（BCAA）催化葡萄糖代谢的转录网络。这些对神经递质生物合成和再循环至关重要的原材料的耗尽导致突触、认知和记忆功能受损;引发经常在LOAD中发现的早期变化。作者还强调，鼻内补充谷氨酰胺和支链氨基酸可有效保护神经元的完整性和脑功能，提出了一种基于营养的方法，用于在LRP 6细胞表面水平和功能不佳时延迟认知和记忆衰退。星形胶质细胞是主要的大脑代谢工具，能量代谢的改变与迟发性阿尔茨海默病有关。差异Wnt下游信号传导调节这些细胞中的代谢景观。鼻内补充谷氨酰胺和支链氨基酸的需求增加可能有助于保护神经元的完整性和大脑功能;这表明了一种基于营养素的替代方法来延缓认知和记忆衰退。
Early changes in astrocyte energy metabolism are associated with late‐onset Alzheimer's disease (LOAD), but the underlying mechanism remains elusive. A previous study suggested an association between a synonymous SNP (rs1012672, C→T) in LRP6 gene and LOAD; and that is indeed correlated with diminished LRP6 gene expression in the frontal cortex region. The authors show that LRP6 is a unique Wnt coreceptor on astrocytes, serving as a bimodal switch that modulates their metabolic landscapes. The Wnt‐LRP6 mediated mTOR‐AKT axis is essential for sustaining glucose metabolism. In its absence, Wnt switches to activate the LRP6‐independent Ca2+‐PKC‐NFAT axis, resulting in a transcription network that favors glutamine and branched chain amino acids (BCAAs) catabolism over glucose metabolism. Exhaustion of these raw materials essential for neurotransmitter biosynthesis and recycling results in compromised synaptic, cognitive, and memory functions; priming for early changes that are frequently found in LOAD. The authors also highlight that intranasal supplementation of glutamine and BCAAs is effective in preserving neuronal integrity and brain functions, proposing a nutrient‐based method for delaying cognitive and memory decline when LRP6 cell surface levels and functions are suboptimal. Astrocytes are the major brain metabolic workhorses and altered energy metabolism is associated with late‐onset Alzheimer's disease. Differential Wnt downstream signaling modulates the metabolic landscape in these cells. Intranasal supplementation of enhanced demand on glutamine and branched‐chain amino acids may help to preserve neuronal integrity and brain functions; suggesting an alternative nutrient‐based method for delaying cognitive and memory decline.
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影响因子：
14.8
作者：
Kelley LA;Mezulis S;Yates CM;Wass MN;Sternberg MJ
通讯作者：
Sternberg MJ
影响因子：
--
作者：
Kumar, Hitesh;Mishra, Gaurav;Gupta, Umesh
通讯作者：
Gupta, Umesh
影响因子：
7.3
作者：
Cselenyi, Christopher S.;Lee, Ethan
通讯作者：
Lee, Ethan
影响因子：
14.9
作者：
Comeau, SR;Gatchell, DW;Camacho, CJ
通讯作者：
Camacho, CJ
DOI：
10.1073/pnas.1711243115
发表时间：
2017-12-26
影响因子：
11.1
作者：
Handley, Renee R.;Reid, Suzanne J.;Snell, Russell G.
通讯作者：
Snell, Russell G.