Death-associated protein kinase 1 mediates A1342 aggregation-induced neuronal apoptosis and tau dysregulation in Alzheimer's disease

The aggregation of amyloid-13 (A13) peptides into oligomers and fibrils is a key pathological feature of Alzheimer's disease (AD). An increasing amount of evidence suggests that oligomeric A13 might be the major culprit responsible for various neuropathological changes in AD. Death-associated protein kinase 1 (DAPK1) is abnormally elevated in brains of AD patients and plays an important role in modulating tau homeostasis by regulating prolyl isomerase Pin1 phosphorylation. However, it remains elusive whether and how A13 species influence the function of DAPK1, and whether this may further affect the function and phosphorylation of tau in neurons. Herein, we demonstrated that A13 aggregates (both oligomers and fibrils) prepared from synthetic A1342 peptides were able to upregulate DAPK1 protein levels and thereby its function through heat shock protein 90 (HSP90)-mediated protein stabilization. DAPK1 activation not only caused neuronal apoptosis, but also phosphorylated Pin1 at the Ser71 residue, leading to tau accumulation and phosphorylation at multiple AD-related sites in primary neurons. Both DAPK1 knockout (KO) and the application of a specific DAPK1 inhibitor could effectively protect primary neurons against A13 aggregate-induced cell death and tau dysregulation, corroborating the critical role of DAPK1 in mediating A13 aggregation-induced neuronal damage. Our study suggests a mechanistic link between A13 oligomerization and tau hyperphosphorylation mediated by DAPK1, and supports the role of DAPK1 as a promising target for early intervention in AD.

Automated summary

The aggregation of A13 peptides into oligomers and fibrils is a key feature of Alzheimer's disease. This study reveals that A13 oligomers can upregulate DAPK1 levels and cause neuronal apoptosis and tau phosphorylation. The inhibition of DAPK1 can protect neurons against A13-induced damage.