Low-Density Lipoprotein Receptor-Related Protein 6 Cell Surface Availability Regulates Fuel Metabolism in Astrocytes

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.