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Title: Low-density lipoprotein receptor-related protein 6 cell surface availability regulates fuel metabolism in astrocytes
Authors: Chow, HM
Sun, JKL
Hart, RP
Cheng, KKY 
Hung, CHL 
Lau, TM
Kwan, KM
Issue Date: Aug-2021
Source: Advanced science, 18 Aug. 2021, 2004993,
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
Metabolic reprogramming
Wnt signaling
Publisher: Wiley-VCH
Journal: Advanced science 
ISSN: 2198-3844
DOI: 10.1002/advs.202004993
Rights: © 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.This is an open access article under the terms of the Creative CommonsAttribution License (, which permits use, distribution and reproduction inany medium, provided the original work is properly cited.
The following publication Chow, H.-M., Sun, J. K.-L., Hart, R. P., Cheng, K. K.-Y., Hung, C. H. L., Lau, T.-M., Kwan, K.-M., Low-Density Lipoprotein Receptor-Related Protein 6 Cell Surface Availability Regulates Fuel Metabolism in Astrocytes. Adv. Sci. 2021, 8, 2004993 is available at
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