EGFR–Annexin A2 signaling–mediated tauopathy in amyloid-β and aluminum chloride–induced Alzheimer’s disease and its modulation by the HDAC inhibitor butyrate

Alzheimer’s disease (AD) is typified by amyloid-β (Aβ) accumulation and tauopathy, culminating in synaptic destabilization, dendritic atrophy, and widespread neurodegeneration. Epidermal growth factor receptor (EGFR), prominently expressed during neurodevelopment, is largely quiescent in adulthood but undergoes pathological reactivation in AD, with its mechanistic contribution remaining elusive. Here, we delineate the EGFR–Annexin A2 (AnxA2) signaling nexus as a pivotal mediator of tau hyperphosphorylation in Aβ₁–₄₂–challenged SH-SY5Y and PC12 neuronal cultures and in aluminum chloride (AlCl₃)/D-galactose (D-gal)–induced AD rat models. In vitro, Aβ₁–₄₂ orchestrated synergistic EGFR–AnxA2 activation, triggering site-specific tau phosphorylation (Thr231/Ser396), synaptic protein depletion, apoptotic cascades, neuroinflammatory signaling, and plasminogen activator inhibitor-1 (PAI-1)–driven fibrinolytic deficits. In vivo, AlCl₃/D-gal rats displayed hippocampal EGFR–AnxA2 upregulation, region-specific tauopathy, cognitive impairments in Open Field and Novel Object Recognition paradigms, oxidative perturbations, and elevated TNF-α. Butyrate intervention abrogated EGFR–AnxA2 hyperactivity, attenuated tau pathology, restored PAI-1/tissue plasminogen activator homeostasis, and mitigated oxidative stress and neuroinflammation. Moreover, butyrate preserved synaptic and dendritic architecture, modulated apoptotic effectors by upregulating Bcl-2 and suppressing Bad, and enhanced neuronal viability. In vivo pre-and post-treatment paradigms improved behavioral and molecular outcomes, with prophylactic administration exhibiting superior efficacy. Collectively, these findings establish EGFR–AnxA2 as a central driver of tauopathy and identify prophylactic butyrate as a mechanistically grounded, diet-derived neuroprotective strategy capable of attenuating tau hyperphosphorylation, synaptic loss, and neuroinflammation in AD.