Thorase deficiency causes both Aβ accumulation and tau hyperphosphorylation in mouse brain

The pathogenesis of two major pathogenic characters-amyloid beta (Aβ) accumulation and hyperphosphorylated tau protein-in the brains of patients with Alzheimer's disease (AD) remains unclear.

Western blot and immunofluorescence staining were performed to detect the proteins in the brains of Thorase conditional knockout/transgenic mice and their littermates. A co-immunoprecipitation assay was applied to examine the Thorase-interacting proteins.

Genetic deletion of Thorase resulted in tau hyperphosphorylation and promoted Aβ accumulation in the mouse brain. Conversely, Thorase overexpression alleviated the pathogenesis of AD. Thorase regulated the phosphorylation of tau by targeting specific kinases and theprotein phosphatase 2B (PP2B). Thorase deficiency also impaired microglial phagocytosis and induced neuroinflammation by the activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasomes in microglia.

Thorase may be a potential druggable target for developing therapeutic approaches to treat AD and other neurodegenerative diseases.

Thorase deletion leads to elevated amyloid beta (Aβ) deposition and hyperphosphorylated tau accumulation in the brain. Thorase regulates the phosphorylation of tau protein via PP2B. Thorase deficiency impairs microglial phagocytosis and promotesNLRP3-mediated neuroinflammation. Overexpression of Thorase alleviates Aβ deposition and tau phosphorylation in the AD mouse model.