Abstract
BackgroundDisruption 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 (PLA2) 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.MethodsAPPswe/PS1dE9 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.ResultsWe show that hemizygous knock in of the overexpressing Prdx6 transgene in APPswe/PS1dE9 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.ConclusionsWe 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.
Highlights
Disruption of β-amyloid (Aβ) homeostasis is the initial culprit in Alzheimer’s disease (AD) pathogenesis
ADassociated variants in Triggering Receptor Expressed in Myeloid cells 2 (TREM2) rendering microglia ineffective in Aβ plaque processing have been identified as second to the APOE ε4 allele genetic risk factor for sporadic AD, highlighting the importance of periplaque glia function in Aβ proteostasis and in arresting downstream cascade of AD neurodegeneration [4]
We found no differences in the morphology of Glial fibrillary acidic protein (GFAP)+ astrocytes and their load in the dentate hilus, which we analyzed in mice aged 3 months (Fig. 1g, h)
Summary
Disruption of β-amyloid (Aβ) homeostasis is the initial culprit in Alzheimer’s disease (AD) pathogenesis. Peroxiredoxin (PRDX) 6 is an enzymatic protein with independent glutathione peroxidase (Gpx) and phospholipase A2 (PLA2) activities involved in repair of oxidatively damaged cell membrane lipids and cellular signaling. In contrast to microglia the role of astrocytes in Aβ proteostasis and plaque formation remains ill-defined, mainly due to a paucity of known factors modulating astrocytic function in AD, and especially those, whose variable expression level would create a tractable experimental model. We decided to explore function of astrocytes in Aβ proteostasis and plaque formation through modulating expression level of an astrocytic native protein peroxiredoxin (PRDX) 6. To explore the function of PRDX6 in Aβ proteostasis we made APPswe/PS1dE9 transgenic (Tg) mice with hemizygous knock in of the overexpressing Prdx transgene and those with Prdx haplodeficiency This experimental design showed that PRDX6 governs a protective function of astrocytes in countering Aβ deposition. Since PRDX6 is an astrocytic protein, the latter observation implies that astrocytes target microglia to Aβ plaques and circuitously regulate microglia dependent Aβ plaque processing
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