AGE-RELATED MYELIN DEFECTS CAUSE BRAIN ACIDIFICATION SUFFICIENT TO IMPAIR AB CLEARANCE BY MICROGLIAL CELLS

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterised by the extracellular amyloid beta (Aβ) plaques, intracellular neurofibrillary tangles and progressive neurodegeneration. Ageing, the primary risk factor of AD, affects at the ultrastructural level the physical integrity of intracortical myelin. In the adult brain, myelin-forming oligodendrocytes metabolically support the axonal compartment by providing pyruvate/lactate via monocarboxylate transporters. We hypothesised that myelin ageing and the physical perturbation of normal neuron-glial metabolic coupling are risk factors for brain health. Indeed, we found that mouse models of amyloidosis (5×FAD; APP^NLGF), in combination with age-related genetic defects of myelin (Cnp^−/−; Plp^−/y), exhibit an exacerbated amyloid pathology (Depp et al., Nature 2023). In the present study, we hypothesised that the loss of myelin integrity causes oligodendrocytes to release pyruvate/lactate into the extracellular space, along with H+ ions, causing extracellular acidification. Such pH changes might contribute to AD pathogenesis by changing the microglial phenotype and ability to phagocytose Aβ. Using an optical fibre pH meter, we measured extracellular pH in aged brain, AD and myelin-defective mice, all of which exhibited a significant decline in brain pH relative to wild-type controls. Next, we examined primary microglia cultures in the presence of fluorescently tagged Aβ peptides under different pH conditions. We found that the microglial uptake of Aβ is progressively impaired with decreased pH, suggesting extracellular brain pH is a modulator of Aβ clearance by microglia. Targeting the acidification of the extracellular milieu could be a promising strategy to prevent or delay AD pathology.