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Background  Disruption of β-amyloid (Aβ) homeostasis is the initial culprit in Alzheimer’s disease (AD) pathogenesis. Astrocytes respond to emerging Aβ plaques by altering their phenotype and function, yet molecular mechanisms governing astrocytic response and their precise role in countering Aβ 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-type  Prdx6  allele or to  Prdx6  knock out mice. Aβ pathology and associated neuritic degeneration were assessed in mice aged 10 months. Laser scanning confocal microscopy was used to characterize Aβ plaque morphology and activation of plaque-associated astrocytes and microglia. Effect of  Prdx6  gene 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 Aβ 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 Aβ load and Aβ-associated neuritic degeneration. Conversely,  Prdx6  haplodeficiency attenuates astro- and microglia activation around Aβ plaques promoting Aβ deposition and neuritic degeneration.    Conclusions  We identify here PRDX6 as an important factor regulating response of astrocytes toward Aβ plaques. Demonstration that phagocytic activation of periplaque microglia vary directly with astrocytic PRDX6 expression level implies previously unappreciated astrocyte-guided microglia effect in Aβ proteostasis. Our showing that upregulation of PRDX6 attenuates Aβ pathology may be of therapeutic relevance for AD.

Peroxiredoxin 6 mediates protective function of astrocytes in Aβ proteostasis