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This study explores how tenascin\u2010R, a myelin\u2010associated protein at nodes of Ranvier (NORs), modulates A\u03b2 generation through Nav1.6 within this cortico\u2010hippocampal circuit.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>We integrated genetic, electrophysiological, and microdialysis techniques in APP\/PS1 mice and constructed tenascin\u2010R gene fragments and GEDC motif to identify potential therapeutic sequences for AD treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Stimulating the entorhinal cortex increased A\u03b2\n                      <jats:sub>1\u201042<\/jats:sub>\n                      release along the perforant pathway through Nav\u2010dependent mechanisms. Reducing tenascin\u2010R decreased A\u03b2 deposition and alleviated cognitive deficits. Overexpressing tenascin\u2010R enhanced Nav1.6 currents and upregulated amyloid precursor protein and \u03b2\u2010secretase. The GEDC motif within tenascin\u2010R's epidermal growth factor\u2013like domain controlled Nav1.6 activity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Our findings demonstrate that NORs signaling modulates A\u03b2 processing independently of synaptic mechanisms. Tenascin\u2010R regulates A\u03b2 pathogenesis via Nav1.6 at NORs, underscoring myelin proteins and Nav1.6 as therapeutic targets. The GEDC motif represents a potential peptide\u2010based compound for AD therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Nodes of Ranvier\u2010associated tenascin\u2010R (Tn\u2010R) regulate amyloid beta (A\u03b2) production in the perforant pathway of APP\/PS1 mice.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Tn\u2010R enhances Nav1.6\u2010mediated sodium currents, promoting amyloid precursor protein (APP) transcription and A\u03b2 generation.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Genetic downregulation of Tn\u2010R mitigates A\u03b2 deposition, restores synaptic integrity, and improves cognition.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The conserved GEDC motif within Tn\u2010R's epidermal growth factor\u2013like domain is critical for modulating Nav1.6 activity and amyloidogenesis.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The Tn\u2010R\/Nav1.6 axis represents a novel therapeutic target for Alzheimer's disease, with GEDC\u2010derived peptides offering translational potential.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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