Author:

Keywords:

ALPHA-SYNUCLEIN, ANIMAL-MODELS, BRAIN, Cell Biology, DISEASE PROGRESSION, ENDOPEPTIDASE INHIBITOR, FRONTOTEMPORAL DEMENTIA, Life Sciences & Biomedicine, Medicine, Research & Experimental, MOUSE MODEL, NEUROFIBRILLARY TANGLES, OXIDATIVE STRESS, PROTEIN PHOSPHATASE 2A, Research & Experimental Medicine, Science & Technology, Mice, Humans, Animals, Prolyl Oligopeptidases, HEK293 Cells, Tauopathies, tau Proteins, Mice, Transgenic, Serine Endopeptidases, Enzyme Inhibitors, Disease Models, Animal, 06 Biological Sciences, 11 Medical and Health Sciences, 3206 Medical biotechnology, 4003 Biomedical engineering

Abstract:

Tauopathies are neurodegenerative diseases that are characterized by accumulation of hyperphosphorylated tau protein, higher-order aggregates, and tau filaments. Protein phosphatase 2A (PP2A) is a major tau dephosphorylating phosphatase, and a decrease in its activity has been demonstrated in tauopathies, including Alzheimer's disease. Prolyl oligopeptidase is a serine protease that is associated with neurodegeneration, and its inhibition normalizes PP2A activity without toxicity under pathological conditions. Here, we assessed whether prolyl oligopeptidase inhibition could protect against tau-mediated toxicity in cellular models in vitro and in the PS19 transgenic mouse model of tauopathy carrying the human tau-P301S mutation. We show that inhibition of prolyl oligopeptidase with the inhibitor KYP-2047 reduced tau aggregation in tau-transfected HEK-293 cells and N2A cells as well as in human iPSC-derived neurons carrying either the P301L or tau-A152T mutation. Treatment with KYP-2047 resulted in increased PP2A activity and activation of autophagic flux in HEK-293 cells and N2A cells and in patient-derived iNeurons, as indicated by changes in autophagosome and autophagy receptor markers; this contributed to clearance of insoluble tau. Furthermore, treatment of PS19 transgenic mice for 1 month with KYP-2047 reduced tau burden in the brain and cerebrospinal fluid and slowed cognitive decline according to several behavioral tests. In addition, a reduction in an oxidative stress marker was seen in mouse brains after KYP-2047 treatment. This study suggests that inhibition of prolyl oligopeptidase could help to ameliorate tau-dependent neurodegeneration.