Suppression of DAPK1 reduces ischemic brain injury through inhibiting cell death signaling and promoting neural remodeling.

The role of death-associated protein kinase1 (DAPK1) in post-stroke functional recovery is controversial, as is its mechanism of action and any neural remodeling effect after ischemia. To assess the debatable role of DAPK1, we established the middle cerebral artery occlusion (MCAo) model in DAPK1 knockout mice and Sprague-Dawley (SD) rats. We identified that the genetic deletion of the DAPK1 as well as pharmacological inhibition of DAPK1 showed reduced brain infarct volume and neurological deficit. We report that DAPK1 inhibition (DI) reduces post-stroke neuronal death by inhibiting BAX/BCL2 and LC3/Beclin1 mediated apoptosis and autophagy, respectively. Histological analysis displayed a reduction in nuclear condensation, neuronal dissociation, and degraded cytoplasm in the DI group. The DI treatment showed enhanced dendrite spine density and neurite outgrowth, upregulated neural proliferation marker proteins like brain-derived neurotrophic factor, and reduced structural abnormalities of the cortical pyramidal neurons. This research shows that DAPK1 drives cell death, its activation exacerbates functional recovery after cerebral ischemia and shows that oxazolone-based DI could be an excellent candidate for stroke and ischemic injury intervention.

Inhibition of death-associated protein kinase 1 attenuates the phosphorylation and amyloidogenic processing of amyloid precursor protein.

Extracellular deposition of amyloid-beta (Aß) peptide, a metabolite of sequential cleavage of amyloid precursor protein (APP), is a critical step in the pathogenesis of Alzheimer's disease (AD). While death-associated protein kinase 1 (DAPK1) is highly expressed in AD brains and its genetic variants are linked to AD risk, little is known about the impact of DAPK1 on APP metabolism and Aß generation. In this study, we demonstrated a novel effect of DAPK1 in the regulation of APP processing using cell culture and mouse models. DAPK1, but not its kinase deficient mutant (K42A), significantly increased human Aß secretion in neuronal cell culture models. Moreover, knockdown of DAPK1 expression or inhibition of DAPK1 catalytic activity significantly decreased Aß secretion. Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of Aß. In Tg2576 APPswe-overexpressing mice, knockout of DAPK1 shifted APP processing toward non-amyloidogenic pathway and decreased Aß generation. Finally, in AD brains, elevated DAPK1 levels showed co-relation with the increase of APP phosphorylation. Combined together, these results suggest that DAPK1 promotes the phosphorylation and amyloidogenic processing of APP, and that may serve a potential therapeutic target for AD.