@article{b29669a5730d41b2bb861b22fd3a5268,
title = "Low-Density Lipoprotein Receptor-Related Protein 6 Cell Surface Availability Regulates Fuel Metabolism in Astrocytes",
abstract = "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.",
keywords = "Alzheimer's disease, amino acid metabolism, astrocyte, metabolic reprogramming, Wnt signaling",
author = "Chow, {Hei Man} and Sun, {Jacquelyne Ka Li} and Hart, {Ronald P.} and Cheng, {Kenneth King Yip} and Hung, {Clara H.L.} and Lau, {Tsun Ming} and Kwan, {Kin Ming}",
note = "Funding Information: The authors would like to thank members of the Chow Laboratory at CUHK; K. Herrup of Pittsburgh University; R. P. Hart, M. Plummer, and Q. Cai of Rutgers University; K. K. Cheng Laboratory; B. K. Yee and C. H. L Hung of the Hong Kong Polytechnic University for their helpful advice, comments, and contribution. They acknowledge the University Research Facility in Life Sciences (ULS) of Hong Kong Polytechnic University; Biosciences Central Research Facility and Animal and Plant Care Facility of the Hong Kong University of Science and Technology; and the Laboratory Animal Services Center (LASEC) of the Chinese University of Hong Kong for technical assistance. The work was supported, in part, by grants from the following: The Hong Kong Research Grants Council (RGC)‐General Research Fund (GRF) (PI: GRF16100219, GRF16100718, and GRF16103317); Alzheimer's Association Research Fellowship (PI: AARF‐17‐531566); Collaborative Research Fund (CRF) (Co‐I: C4033‐19EF); CUHK‐Improvement on Competitiveness in Hiring New Faculties Funding Scheme (PI: Ref. 133) and CUHK‐School of Life Sciences Startup funding to H.‐M.C. Funding Information: The authors would like to thank members of the Chow Laboratory at CUHK; K. Herrup of Pittsburgh University; R. P. Hart, M. Plummer, and Q. Cai of Rutgers University; K. K. Cheng Laboratory; B. K. Yee and C. H. L Hung of the Hong Kong Polytechnic University for their helpful advice, comments, and contribution. They acknowledge the University Research Facility in Life Sciences (ULS) of Hong Kong Polytechnic University; Biosciences Central Research Facility and Animal and Plant Care Facility of the Hong Kong University of Science and Technology; and the Laboratory Animal Services Center (LASEC) of the Chinese University of Hong Kong for technical assistance. The work was supported, in part, by grants from the following: The Hong Kong Research Grants Council (RGC)-General Research Fund (GRF) (PI: GRF16100219, GRF16100718, and GRF16103317); Alzheimer's Association Research Fellowship (PI: AARF-17-531566); Collaborative Research Fund (CRF) (Co-I: C4033-19EF); CUHK-Improvement on Competitiveness in Hiring New Faculties Funding Scheme (PI: Ref. 133) and CUHK-School of Life Sciences Startup funding to H.-M.C. Publisher Copyright: {\textcopyright} 2021 The Authors. Advanced Science published by Wiley-VCH GmbH",
year = "2021",
month = aug,
doi = "10.1002/advs.202004993",
language = "English",
volume = "8",
journal = "Advanced Science",
issn = "2198-3844",
publisher = "Wiley-VCH Verlag",
number = "16",
}