Role of Peroxiredoxin 6 in the Development of Tau Pathology

Abstract

AbstractBackgroundIn Alzheimer’s disease (AD) and fronto‐temporal dementia excess of hyperphosphorylated tau (p‐tau) assembles into neurofibrillary tangles (NFTs). NFT‐bearing neurons are associated with A1 neurotoxic astrocytes and neurodegenerative phenotype microglia (MGnD). A1 astrocytes lose their neuron‐supporting properties and along with MGnD contribute importantly to the degeneration of NFT‐bearing neurons. MGnD and A1 astrocytes also reciprocally stimulate their pathological phenotypes. Factors endowing astrocytes with resistance to A1 transformation remain unknown. Astrocytes express peroxiredoxin 6 (PRDX6) protein, which glutathione peroxidase and phospholipase 2 enzymatic activities enable repair of oxidatively damaged cell membranes and cell‐to‐cell signaling. PRDX6 upregulation has been noted in astrocytes associated with NFT‐bearing neurons in AD, yet its precise role in the development of tau pathology remains unknown. To this end we created new MAPTP301S transgenic mouse lines featuring Prdx6 haplodeficiency and hemizygous knock‐in of the overexpressing Prdx6 transgene.MethodMAPTP301S (PS19/Prdx6+/+) mice were crossed with Prdx6−/− mice and with Prdx6129X1/SvJ allele knock‐in mice, which feature wild‐type PRDX6 overexpression. Resulting lines PS19/Prdx6+/−, PS19/Prdx6+/+, and PS19/Prdx6Tg showed 0.4:1:2 ratio of brain Prdx6 mRNA level, while hTau and Gfap mRNA levels were similar. All lines were neuropathologically characterized at the age of 9.5 months.ResultBrain atrophy determined by quantifying hippocampal and lateral ventricular volumes and the hippocampal p‐tau load show inverse relations with the Prdx6 gene dose. The load of GFAP+ astrocytes and the C3+/GFAP+ ratio used as a surrogate A1 phenotype marker also vary inversely with the Prdx6 expression. The load of IBA1+ microglia show inverse relation with the Prdx6 gene dose, while the CD68+/IBA1+ index used as a surrogate marker of microglia phagocytic activity show direct correlation.ConclusionAttenuation of the pathological phenotype in PS19/Prdx6Tg line and its worsening in PS19/Prdx6+/− line evidence a neuroprotective role of PRDX6 in tau‐mediated neurodegeneration. Observed inverse relation between the Prdx6 gene dose and astrocytic C3 expression and microglia activation suggests PRDX6 endows astrocytes with resistance to A1 transition, which in turn hampers microglia activation. Analysis of astrocyte and microglia transcript from PS19/Prdx6+/−, PS19/Prdx6+/+, and PS19/Prdx6Tg lines focused on A1 and MGnD activation markers is underway.