Metabolic reallocation in spinal cord oligodendrocytes drives chronic pain via neuronal β-amyloid production

Abstract

Peripheral injury reprograms metabolism in spinal cord oligodendrocytes, initiating a molecular cascade that drives chronic pain via neuronal {beta}-amyloid (A{beta}) release. After injury, mouse spinal oligodendrocytes downregulate myelin protein synthesis and upregulate lipid biosynthesis--but reroute lipids toward neuroplastic remodeling and away from myelin maintenance. This metabolic reallocation disrupts myelin integrity and axonal function, causing neuronal accumulation of amyloid precursor protein, enhanced expression of its processing {beta}-secretase BACE1, and local release of A{beta} peptides. Blocking A{beta} production or clearing A{beta} deposits stops the transition to pain chronicity. Deleting the lysosomal lipid hydrolase NAAA in oligodendrocytes prevents both injury-induced A{beta} production and chronic pain development. The findings identify an unexpected mechanistic link between chronic pain and Alzheimers-like neurodegeneration, positioning A{beta} as a target for therapeutic intervention.