Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
Tenascin-R aggravates Aβ production in the perforant pathway by regulating Nav1.6 activity in APP/PS1 mice.
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Wang Bin, Wang Zhi-Xue, Lv Lang-Man, Wang Xi, Lu Jin-Cheng, Zhao Yi-Fan, Jiang Rong, Li Qi-Fa, Kong Yue, Yang Xue-Wei, Luo Jie, Xiao Zhi-Cheng, Li Ai-Ping, Yang Guang, Ma Quan-Hong, Shao Li
Аннотация
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 Aβ1-42 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.
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 Aβ1-42 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.