Retromer‐dependent mechanisms of tau dysregulation in Down syndrome

Abstract

AbstractBackgroundDeficiencies in the retromer complex are reported in brains of Down syndrome subjects, and retromer protein levels inversely correlate with amyloidosis. The complex is also proposed to influence tau levels, however, the relationship between tau neuropathology and retromer deficiency in Down syndrome remains unclear. In the current study, we examine the relationship between pathological tau and retromer deficiency and explore potential mechanisms involved.MethodsPost‐mortem brain tissues from Down syndrome and control subjects were evaluated for retromer proteins, pathological tau and proteins relevant to its post‐translational modification. To explore potential mechanisms of retromer‐dependent effects on tau, neuro‐2A cells overexpressing human tau were treated with the pharmacological chaperone, TPT‐172, with or without the CDK5 inhibitor, roscovitine.ResultsPhosphorylated epitopes and insoluble forms tau were elevated in brain tissues of subjects with Down syndrome and inversely correlated with retromer proteins and the activity of cathepsin D. In vitro pharmacological stabilization of the retromer complex with TPT‐172 resulted in decreased levels of phosphorylated tau and the CDK5 activating protein, p25. The effect on tau phosphorylation was neutralized by incubation with the CDK5 inhibitor, roscovitine. Furthermore, CDK5‐p25 immunoprecipitated from cells treated with TPT‐172 caused significantly less histone phosphorylation, indicating that the treatment reduced CDK5 activity.ConclusionWe conclude that in Down syndrome deficiency of retromer proteins is involved in the development of tau neuropathology. We propose that retromer dysfunction contributes to the development of tau pathology by decreasing the degradative lysosomal pathway and by increasing phosphorylation via CDK5. Because pharmacological stabilization of the retromer complex decreases tau phosphorylation, we propose this could represent a novel therapy against tau pathology in Down syndrome.