BACKGROUND: Pathological deposition of hyperphosphorylated tau in the brain closely correlates with the course of Alzheimer's disease (AD). Tau pathology occurs in axons of affected neurons and tau removal from axons might thus be an early intervention strategy. METHODS: We investigated the role of the RNA-binding protein hnRNP R in axonal localization and local translation of Mapt mRNA in neurons cultured from hnRNP R knockout mice. hnRNP R knockout mice were crossed with 5ÃFAD mice, an AD mouse model, and the effects of hnRNP R loss on the deposition of phospho-tau and amyloid-β plaques were evaluated. We designed antisense oligonucleotides (MAPT-ASOs) to block the binding of hnRNP R to Mapt mRNA. Cultured mouse and human neurons were treated with MAPT-ASOs and axonal Mapt mRNA and tau protein levels were quantified. MAPT-ASO was injected intracerebroventricularly into 5ÃFAD mice followed by quantification of phospho-tau aggregates and amyloid-β plaques in their brains. Protein changes in brains of 5ÃFAD mice treated with the MAPT-ASO were measured by mass spectrometry. RESULTS: Mapt mRNA and tau protein were reduced in axons but not cell bodies of primary neurons cultured from hnRNP R knockout mice. Brains of 5ÃFAD mice deficient for hnRNP R contained less phospho-tau aggregates and amyloid-β plaques in the cortex and hippocampus. Treatment of neurons with MAPT-ASOs to block hnRNP R binding to Mapt similarly reduced axonal tau levels. Intracerebroventricular injection of a MAPT-ASO reduced the phospho-tau and plaque load and prevented neurodegeneration in the brains of 5ÃFAD mice, accompanied by rescue of proteome alterations. CONCLUSION: Lowering of tau selectively in axons thus represents an innovative therapeutic perspective for treatment of AD and other tauopathies.
Axonal tau reduction ameliorates tau and amyloid pathology in a mouse model of Alzheimer's disease.
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作者:Zare Abdolhossein, Salehi Saeede, Bader Jakob M, Wiessler Anna-Lena, Prokesch Manuela, Albrecht Vincent, Villmann Carmen, Mann Matthias, Briese Michael, Sendtner Michael
期刊: | Translational Neurodegeneration | 影响因子: | 15.200 |
时间: | 2025 | 起止号: | 2025 Jul 29; 14(1):39 |
doi: | 10.1186/s40035-025-00499-0 |
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