Targeting APT2 to Enhance Tau Palmitoylation and Reprogram the Neuroimmune Landscape for Cognitive Restoration in Alzheimer's Disease
Description
Alzheimer's disease (AD) remains a formidable therapeutic challenge, largely because interventions targeting isolated pathological features have shown limited efficacy. Here, we identify dynamic palmitoylation of Tau as a regulatory mechanism that integrates the core pathological triad of AD: Tau dysfunction, neuroinflammation, and synaptic impairment. Tau palmitoylation is governed by the palmitoyltransferase ZDHHC23 and the depalmitoylating enzyme APT2. In both 5xFAD mice and human AD brains, Tau palmitoylation is markedly diminished. Mechanistically, without altering Aβ levels, genetic or pharmacological inhibition of APT2 enhances Tau palmitoylation, stabilizes Tau–microtubule interactions, suppresses disulfide bond–mediated oligomerization, and restores neuronal morphology and cognitive function. Single-nucleus RNA sequencing reveals that APT2 loss reprograms neuronal and microglial populations, underscoring the convergence of inflammatory and synaptic pathways. Notably, enhancing Tau palmitoylation in neurons remodels the neuroimmune landscape and rescues cognition independently of changes in amyloid-beta levels. These findings position APT2 inhibition as a promising therapeutic strategy for AD.
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Institutions
- First Affiliated Hospital of Xinxiang Medical UniversityChongqing, Xinxiang