Klotho is a neuroprotective protein associated with neurodegenerative disorders. Klotho mRNA is spliced into canonical and alternate transcripts. Expression ratio between these was associated with pathological conditions in kidney. While Klotho's functions in the kidney are well established, its mechanisms of action in the brain remain elusive. Klotho modulates brain neuroinflammation and mediates the crosstalk between immune system and central nervous system.
Total Klotho expression and alternative/canonical ratio were compared in monocyte-derived microglia (MDMi), neural progenitor cells (ReNcell VM) and peripheral blood mononuclear cells (PBMCs). MDMi cultured from PBMCs were subjected to differentiation using growth factors. MDMi generated from Healthy control (HC), AD, HC treated with β-amyloid (Aβ) and bushfire (BF), untreated ReNcells and PBMCs were used.
Overall, Klotho expression varied among groups. ReNcell showed low expression, while HC and AD MDMi showed similar levels, except for one high-expression AD individual. Similarly, MDMi treated with Aβ and BF had comparable Klotho expression with one outlier each. PBMCs showed great variability, with one individual showing minimal Klotho expression and other having the highest. Transcript ratio analysis indicated predominance of canonical over alternative Klotho in almost all samples. AD, Aβ and ReNcell showed lower alternative/canonical ratios. This suggests potential differences in Klotho splicing patterns across conditions.
Klotho expression in human microglia in highly variable, particularly under pro-inflammatory conditions. While kidney alternative/canonical Klotho ratio is higher under pathological conditions, the opposite trend was observed in microglia. These results raise questions Klotho's mechanism in the brain and its implications for brain health and disease.