Prevention of tau accumulation through inhibition of hnRNP R-dependent axonalMaptmRNA localization

Abstract

Deposition of neurofibrillary tangles composed of hyperphosphorylated tau in the brain is a pathological hallmark and closely correlates with onset and course of Alzheimer's disease. While tau reduction is being pursued as therapeutic strategy, prolonged lowering of total tau might lead to adverse effects, necessitating the development of more targeted approaches. We report that the RNA-binding protein hnRNP R facilitates the axonal localization of the Mapt mRNA encoding tau. Depletion of hnRNP R reduces tau in axons but not neuronal cell bodies. Brains of Alzheimer's disease mice deficient for hnRNP R contain less tau tangles and amyloid-beta plaques. Neurons treated with blocking antisense oligonucleotides to mask hnRNP R binding sites of Mapt mRNA show reduced axonal tau levels, similar to hnRNP R-deficient neurons. Lowering of tau levels selectively in axons, a major subcellular site of tangle formation and spreading, thus represents a novel therapeutic perspective for treatment of Alzheimer's disease.