Metabolic reprogramming in Alzheimer's disease: Interaction between receptor tyrosine kinase signaling, noncoding RNAs, and Neuron-Glia energy networks.

Alzheimer's disease (AD) is increasingly understood as a disorder involving impaired brain energy metabolism rather than being solely caused by amyloid and tau pathology. This chapter offers a comprehensive overview of how glucose hypometabolism, mitochondrial dysfunction, and disrupted neuron-astrocyte metabolic coupling collectively creates an "energy crisis" in vulnerable neuronal circuits. Early issues with glucose transport (GLUT1/3/4), reduced glycolytic flux, TCA cycle problems, and excessive mitochondrial fission all contribute to decreased ATP production and increased oxidative stress. Along with these metabolic disturbances, receptor tyrosine kinase (RTK) pathways-including insulin/IGF-1, TrkB/BDNF, FGFRs, and EGFR-lose their regulatory control, leading to insulin resistance, synaptic failure, and increased vulnerability to Aβ and tau toxicity. The chapter also highlights noncoding RNAs (miRNAs and lncRNAs) as key post-transcriptional regulators of metabolic and RTK signaling networks. Harmful miRNAs (such as miR-34a, miR-210-3p) suppress glycolytic enzymes and mitochondrial genes, while protective miRNAs (miR-23a/b, miR-455-3p, miR-195) decrease in AD. Metabolic lncRNAs, like EPB41L4A-AS1, decline with age and contribute to NAD⁺ depletion and bioenergetic imbalance. Recognizing the link between RTK dysregulation and ncRNA-driven metabolic control reveals new therapeutic possibilities to restore mitochondrial function, enhance neurotrophic support, and re-establish energy balance in the AD brain.