A Novel PROTAC Confers a Dual Benefit Against Amyloid and Tau Pathology in Alzheimer's Disease via DAPK1 Degradation.

Alzheimer's disease (AD) is a neurodegenerative disorder that is caused by multiple factors, characterized by a progressive decline in cognitive ability, extracellular amyloid-β (Aβ) plaques, and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. Current treatment strategies can provide only symptomatic treatment or limited efficacy, highlighting the need to intervene in the upstream regulatory factors that drive both amyloid and tau pathologies. Death-associated protein kinase 1 (DAPK1) is a key driver upstream of both amyloid precursor protein processing and tau phosphorylation, simultaneously promoting amyloidogenesis and tau-mediated pathology in AD. In this study, we developed CP1, a bifunctional proteolysis-targeting chimera (PROTAC), to recruit E3 ubiquitin ligase to DAPK1, thereby inducing the ubiquitination and proteasomal degradation of DAPK1. CP1 efficiently eliminated the DAPK1 protein in primary cortical neurons without affecting its mRNA level, resulting in reduced Aβ generation and tau hyperphosphorylation. In vivo, upon systemic administration, CP1 effectively crossed the blood-brain barrier, degraded DAPK1, and consequently reduced the Aβ plaque burden and mitigated neuroinflammation in female 5xFAD mice. In a AAV-hTau-P301L tauopathy model, CP1 treatment suppressed tau hyperphosphorylation, preserved NeuN- and MAP2-positive neurons, attenuated astrocytic and microglial activation, and ultimately restored learning and memory abilities in both male and female mice. In summary, these findings demonstrate that degrading DAPK1 via a PROTAC strategy simultaneously mitigates both amyloid and tau pathology, indicating that CP1 is an effective candidate for disease-modifying therapy.