Axonal tau reduction ameliorates tau and amyloid pathology in a mouse model of Alzheimer's disease

BackgroundPathological 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.MethodsWe 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 5xFAD mice, an AD mouse model, and the effects of hnRNP R loss on the deposition of phospho-tau and amyloid-beta 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 5xFAD mice followed by quantification of phospho-tau aggregates and amyloid-beta plaques in their brains. Protein changes in brains of 5xFAD mice treated with the MAPT-ASO were measured by mass spectrometry.ResultsMapt mRNA and tau protein were reduced in axons but not cell bodies of primary neurons cultured from hnRNP R knockout mice. Brains of 5xFAD mice deficient for hnRNP R contained less phospho-tau aggregates and amyloid-beta 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 5xFAD mice, accompanied by rescue of proteome alterations.ConclusionLowering of tau selectively in axons thus represents an innovative therapeutic perspective for treatment of AD and other tauopathies.