Peroxiredoxin 6 mediates protective function of astrocytes in Aβ proteostasis

Abstract

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 (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. Methods APPswe/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. Results We 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. 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.

Lack of the peroxiredoxin 6 gene causes impaired spatial memory and abnormal synaptic plasticity

“…Upregulation of PSD95 in the hippocampus of Prdx6 −/− mice could be the cause of excessive ERK1/2 phosphorylation during memory retrieval. PRDX6 is dominantly expressed in the astrocytes within the hippocampus [ 66 ] and regulates their functions [ 67 ]. Astrocytes are well known to play a critical role in synaptic plasticity [ 25 ], and a decrease in the reactive form of astrocytes is associated with upregulation of PSD95 [ 68 , 69 ].…”

“…Astrocytes are well known to play a critical role in synaptic plasticity [ 25 ], and a decrease in the reactive form of astrocytes is associated with upregulation of PSD95 [ 68 , 69 ]. Previous reports revealed that lack of PRDX6 causes downregulation of the cytokines such as TNF-α [ 15 ] and IL-6 [ 29 ], as well as GFAP, a reactive astrocyte marker [ 67 ]. Here, we detected downregulation of these molecules, particularly GFAP, indicating decreased reactive astrocytes in the hippocampi of Prdx6 −/− mice.…”

Peroxiredoxin 6 Knockout Mice Demonstrate Anxiety Behavior and Attenuated Contextual Fear Memory after Receiving Acute Immobilization Stress

“…Additionally, H 2 O 2 can be reduced to water and oxygen either by catalase (CAT) or glutathione peroxidase (GPx) [ 62 ]. Since PRDX6 exerts GPx activity that can reduce H 2 O 2 [ 63 , 64 ], it is not surprising that PRDX6 depletion gives rise to the excessive level of H 2 O 2 in the hippocampus, basolateral amygdala and medial prefrontal cortex of Prdx6 −/− mice. Subjecting the mice to 30 min of AIS is insufficient to reduce H 2 O 2 level in the prefrontal cortex to wild-type level.…”

Absence of Apolipoprotein E is associated with exacerbation of prion pathology and promotes microglial neurodegenerative phenotype

“…Randomly selected series of sections were immunostained against the following antigens: (1) apoE and GFAP in combination, (2) apoE and Iba1 in combination, (3) PrP, (4) GFAP, (5) C3 and GFAP in combination, (6) Iba1 with 4’, 6’-diamidino-2-phenylindole (DAPI), (7) CD68, (8) CD68 and Iba1 in combination, (9) TREM2 and Iba1 in combinations, (10) NeuN, and Iba1, and CD68 in combination, and (11) TMEM119. Prior to immunostaining the sections were incubated in 10 mM sodium citrate and 0.05% Tween 20 (pH 6.0) at 85 °C for 15 min to increase antigen availability [ 58 ]. For anti-PrP immunostaining the sections were additionally treated with 98% formic acid at room temperature for 10 min.…”

“…When the mouse primary antibody was used, 1μL of the mouse on mouse blocking reagent (Vector Laboratories; Burlingame, CA) was added to 1.5 mL of the blocking solution. For TREM2 immunohistochemistry the specific blocking solution consisted of 5% donkey serum in 10 mM PBS (pH 7.4) and 0.3% Triton X-100 [ 58 ]. For the protocols utilizing biotinylated secondary antibody the blocking was with 5% BSA in 10 mM PBS (pH 7.4) and 0.3% Triton X-100 followed by Avidin/Biotin Blocking Kit (Vector Laboratories).…”