Selective degradation of DAPK1 via a novel hydrophobic tagging attenuates tau pathology in Alzheimer's disease.

introductionThe upregulation of death-associated protein kinase 1 (DAPK1) is involved in tau hyperphosphorylation, neuronal apoptosis and cognitive dysfunction, which are key pathological features of Alzheimer's disease (AD). This result suggests that DAPK1 is novel therapeutic target for AD.

objectivesThis study aimed to evaluate the efficacy and mechanism of action of CJ1, a novel hydrophobic tagging (HyT)-based degrader, in targeting DAPK1 and alleviating in AD.

methodsA library of HyT-based bifunctional molecules was synthesized and systematically screened for their ability to degrade DAPK1 in vitro. CJ1 emerged as the most potent candidate degrader of DAPK1, and its capacity to induce DAPK1 degradation via the proteasome system was further evaluated. Its effects on tau phosphorylation and neuronal viability were evaluated in multiple cellular models. The in vivo efficacy of systemic CJ1 administration was assessed in two tau-related pathology (tauopathy) mouse models, AAV-hTau-P301L and hTau transgenic mice. Behavioral, biochemical, and histological analyses were performed to evaluate cognitive function, tau pathology, neuroinflammation, neurodegeneration, and safety.

resultsCJ1 selectively promoted the posttranslational degradation of DAPK1 by the proteasome system without affecting DAPK1 mRNA expression. In vitro studies demonstrated that CJ1 significantly reduced tau phosphorylation at multiple AD-related sites. In vivo, CJ1 effectively penetrated the blood-brain barrier, decreased the levels of both the soluble and insoluble forms of hyperphosphorylated tau, and suppressed the formation of neurofibrillary tangles. Additionally, CJ1 treatment restored synaptic and dendritic structures, enhanced spatial learning and memory, attenuated neuroinflammatory responses, preserved neuronal populations, and produced no evidence of systemic toxicity.

conclusionCJ1 functions as a potent and selective degrader of DAPK1, exerting neuroprotective effects by reducing tau hyperphosphorylation and preserving neuronal structural integrity. These findings support DAPK1 as a promising therapeutic target and suggest that further preclinical studies are warranted to evaluate CJ1 as a potential treatment for tauopathies associated with AD.