Retromer deficiency is reported in Down syndrome and correlates with amyloidosis, however, its association with tau neuropathology remains unclear. Down syndrome and control brain tissues were evaluated for phosphorylated tau, tau modulators, and cathepsin-D activity. Several kinases and phosphatase PP2A were unchanged, but tau phosphorylation was elevated, and cathepsin-D activity decreased in aged patients with Down syndrome. Retromer proteins positively associated with soluble tau, whereas pathogenic tau negatively correlated with retromer proteins and cathepsin-D activity. Retromer deficiency and consequent reduction of cathepsin-D activity may contribute to pathogenic tau accumulation, thus, retromer represents a viable therapeutic target against tau pathology in Down syndrome. ANN NEUROL 2022;91:561-567.
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