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

Area of Science:

• Neuroscience
• Metabolic pathways
• Alzheimer's disease research

Background:

• Early astrocyte energy metabolism changes are linked to late-onset Alzheimer's disease (LOAD).
• A synonymous single nucleotide polymorphism (SNP) in the LRP6 gene (rs1012672) is associated with LOAD and reduced LRP6 expression in the frontal cortex.
• The precise mechanism connecting astrocyte metabolism and LOAD pathogenesis is not fully understood.

Purpose of the Study:

• To elucidate the role of LRP6 in astrocyte energy metabolism and its connection to LOAD.
• To investigate the signaling pathways regulated by LRP6 in astrocytes.
• To explore potential therapeutic strategies for mitigating cognitive decline associated with LRP6 dysfunction.

Main Methods:

• Investigated LRP6 as a Wnt coreceptor in astrocytes.
• Analyzed the modulation of astrocyte metabolic landscapes by LRP6.
• Examined the Wnt-LRP6 mediated mTOR-AKT axis and the LRP6-independent Ca2+-PKC-NFAT axis.
• Assessed the impact of altered metabolic pathways on neurotransmitter biosynthesis and cognitive functions.
• Evaluated the efficacy of intranasal glutamine and BCAA supplementation.

Main Results:

• LRP6 acts as a bimodal switch in astrocytes, regulating energy metabolism.
• The Wnt-LRP6/mTOR-AKT pathway sustains glucose metabolism.
• In LRP6 absence, the Wnt/Ca2+-PKC-NFAT pathway promotes glutamine and BCAA catabolism over glucose.
• This metabolic shift depletes essential precursors for neurotransmitter synthesis, impairing synaptic and cognitive functions.
• Intranasal glutamine and BCAA supplementation preserved neuronal integrity and brain function in a model of suboptimal LRP6 function.

Conclusions:

• LRP6 dysfunction in astrocytes alters energy metabolism, favoring amino acid catabolism and contributing to LOAD pathogenesis.
• The identified metabolic pathways provide insights into early LOAD mechanisms.
• Nutrient supplementation with glutamine and BCAAs offers a potential therapeutic approach to delay cognitive decline in individuals with impaired LRP6 function.