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.
Highlights
Alzheimer’s disease (LOAD), but the underlying mechanism remains elusive
Our work demonstrates how the coreceptor LRP6 serves as a bimodal switch that regulates Wnt downstream signaling and metabolic network in astrocytes
The net result of such metabolic remodeling is the exhaustion of these key amino acids in the microenvironment that are normally needed for maintaining the synaptic homeostasis and function
Summary
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 correlated with diminished LRP6 gene expression in the frontal cortex region. Wnt switches to activate the LRP6-independent Ca2+-PKC-NFAT axis, resulting in a transcription network that favors glutamine and branched noticed.[2] Populational studies indicated that different metabolic-related risk factors contribute to accelerated age-related cognitive decline and even LOAD.[3] Recent studies indicated that Wnt signaling may chain amino acids (BCAAs) catabolism over glucose metabolism. Knockdown of Lpr switches Wnt signal to the coreceptor-independent calcium-planar cell polarity (PCP)-NFAT axis; thereby reprograms the cellular metabolic dependence on glucose to glutamate-derived glutamine and branched chain amino acids (BCAAs). By a nutrient-based approach, we uncovered that the neurotoxic effect of LRP6 loss is predominantly metabolic, as intranasal supplementations of glutamine and BCAAs were beneficial in preserving physiological and functional integrity of neurons, suggesting an unconventional but feasible way for delaying cognitive and memory decline
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call