Tenascin-R aggravates Aβ production in the perforant pathway by regulating Nav1.6 activity in APP/PS1 mice.

INTRODUCTION: Alzheimer's disease (AD) neuropathology exhibits early accumulation of amyloid beta (Aβ) plaques within the perforant pathway. This study explores how tenascin-R, a myelin-associated protein at nodes of Ranvier (NORs), modulates Aβ generation through Nav1.6 within this cortico-hippocampal circuit. METHODS: We integrated genetic, electrophysiological, and microdialysis techniques in APP/PS1 mice and constructed tenascin-R gene fragments and GEDC motif to identify potential therapeutic sequences for AD treatment. RESULTS: Stimulating the entorhinal cortex increased Aβ(1-42) release along the perforant pathway through Nav-dependent mechanisms. Reducing tenascin-R decreased Aβ deposition and alleviated cognitive deficits. Overexpressing tenascin-R enhanced Nav1.6 currents and upregulated amyloid precursor protein and β-secretase. The GEDC motif within tenascin-R's epidermal growth factor-like domain controlled Nav1.6 activity. DISCUSSION: Our findings demonstrate that NORs signaling modulates Aβ processing independently of synaptic mechanisms. Tenascin-R regulates Aβ pathogenesis via Nav1.6 at NORs, underscoring myelin proteins and Nav1.6 as therapeutic targets. The GEDC motif represents a potential peptide-based compound for AD therapy. HIGHLIGHTS: Nodes of Ranvier-associated tenascin-R (Tn-R) regulate amyloid beta (Aβ) production in the perforant pathway of APP/PS1 mice. Tn-R enhances Nav1.6-mediated sodium currents, promoting amyloid precursor protein (APP) transcription and Aβ generation. Genetic downregulation of Tn-R mitigates Aβ deposition, restores synaptic integrity, and improves cognition. The conserved GEDC motif within Tn-R's epidermal growth factor-like domain is critical for modulating Nav1.6 activity and amyloidogenesis. The Tn-R/Nav1.6 axis represents a novel therapeutic target for Alzheimer's disease, with GEDC-derived peptides offering translational potential.