Peroxiredoxin 6 Regulates Glia Toxicity in Tau Mediated Neurodegeneration

Background In Alzheimer’s disease (AD) neurons, which accumulate hyperphosphorylated tau (p‐tau) are associated with neurodegenerative phenotype microglia (MGnD) and A1 neurotoxic astrocytes. MGnD display reduced ability to phagocytose p‐tau aggregates and neuronal remnants, while their pro‐inflammatory character furthers p‐tau accumulation and neuronal demise. Likewise, A1 astrocytes lose their neuron‐supporting function and promote neurodegeneration. Importantly, MGnD and A1 astrocytes reciprocally stimulate their pathological phenotypes. Factors protecting astrocytes form A1 phenotype transformation are unknown. In this work we explored the role of peroxiredoxin (PRDX) 6 in tau mediated neurodegeneration. PRDX6 is an enzymatic protein which in the CNS is unique to astrocytes. It possesses independent glutathione peroxidase and phospholipase 2 enzymatic activities, which confer ability to repair oxidatively damaged cell membranes and cell‐to‐cell signaling. Method MAPT P301S mutant mice (PS19/Prdx6 +/+) were once crossed to Prdx6 ‐/‐ mice and mice homozygous for the knock‐in of the Prdx6 129X1/SvJ allele overexpressing wild‐type PRDX6 to generate novel PS19/Prdx6 +/‐ and PS19/Prdx6 Tg lines, respectively. Eight weeks old PS19/Prdx6 +/‐, PS19/Prdx6 +/+, and PS19/Prdx6 Tg animals show 0.4:1:2 ratio of Prdx6 brain mRNA level, while levels of hTau and Gfap mRNA remain unchanged. Male mice were neuropathologically characterized at the age of 9.5 months. Result PS19/Prdx6 +/‐ mice feature increased hippocampal atrophy and ventricular enlargement and greater p‐tau accumulation compared to PS19/Prdx6 +/+ mice. Contrariwise, PS19/Prdx6 Tg animals show attenuated brain atrophy and p‐tau accumulation. The GFAP+ load used as a marker of global astrocytic activation and the C3+/GFAP+ ratio, used as a surrogate A1 phenotype marker, vary inversely with the Prdx6 gene dose. Likewise, the load of IBA1+ microglia vary inversely with the Prdx6 gene dose, while the CD68+/IBA1+ index, which determines relative microglia phagocytic activity, directly correlates with the Prdx6 expression. Conclusion Exacerbation of the pathological phenotype in PS19/Prdx6 +/‐ mice reveals a neuroprotective effect of PRDX6 in tau mediated neurodegeneration, while attenuation of pathology in PS19/Prdx6 Tg mice suggests a merit of therapeutic PRDX6 upregulation. PRDX6 endows astrocytes with resistance to A1 phenotype transition. Astrocytic PRDX6 also reprograms microglia by downregulating their g