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

Pathological deposition of hyperphosphorylated tau in the brain closely correlates with the course of Alzheimer´s disease (AD). Tau pathology occurs first in axons of affected neurons and tau removal from axons might thus be an early intervention strategy. We report that the RNA-binding protein hnRNP R facilitates the axonal localization of the Mapt mRNA encoding tau. Mapt 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-β plaques in cortex and hippocampus. Treatment of neurons with antisense oligonucleotides (MAPT-ASOs) to block hnRNP R binding to Mapt similarly reduced axonal tau levels, and intracerebroventricular injection of a MAPT-ASO ameliorated the phospho-tau and plaque load in 5xFAD mice. Lowering of tau selectively in axons thus represents an innovative therapeutic perspective for treatment of AD and other tauopathies.