Peroxiredoxin 6 mediates protective function of astrocytes in Aβ proteostasis

Background: Disruption of beta-amyloid (A beta) homeostasis is the initial culprit in Alzheimer's disease (AD) pathogenesis. Astrocytes respond to emerging A beta plaques by altering their phenotype and function, yet molecular mechanisms governing astrocytic response and their precise role in countering A beta deposition remain ill-defined. Peroxiredoxin (PRDX) 6 is an enzymatic protein with independent glutathione peroxidase (Gpx) and phospholipase A2 (PLA(2)) activities involved in repair of oxidatively damaged cell membrane lipids and cellular signaling. In the CNS, PRDX6 is uniquely expressed by astrocytes and its exact function remains unexplored. Methods: APPswe/PS1(dE9)AD transgenic mice were once crossed to mice overexpressing wild-typePrdx6allele or toPrdx6knock out mice. A beta pathology and associated neuritic degeneration were assessed in mice aged 10 months. Laser scanning confocal microscopy was used to characterize A beta plaque morphology and activation of plaque-associated astrocytes and microglia. Effect ofPrdx6gene dose on plaque seeding was assessed in mice aged six months. Results: We show that hemizygous knock in of the overexpressing Prdx6 transgene in APP(swe)/PS1(dE9) AD transgenic mice promotes selective enticement of astrocytes to A beta plaques and penetration of plaques by astrocytic processes along with increased number and phagocytic activation of periplaque microglia. This effects suppression of nascent plaque seeding and remodeling of mature plaques consequently curtailing brain A beta load and A beta-associated neuritic degeneration. Conversely,Prdx6haplodeficiency attenuates astro- and microglia activation around A beta plaques promoting A beta deposition and neuritic degeneration. Conclusions: We identify here PRDX6 as an important factor regulating response of astrocytes toward A beta plaques. Demonstration that phagocytic activation of periplaque microglia vary directly with astrocytic PRDX6 expression level implies previously unappreciated astrocyte-guided microglia effect in A beta proteostasis. Our showing that upregulation of PRDX6 attenuates A beta pathology may be of therapeutic relevance for AD.