Dataset Information

Peroxiredoxin 6 mediates protective function of astrocytes in A? proteostasis.

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

SUBMITTER: Pankiewicz JE

PROVIDER: S-EPMC7487614 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Peroxiredoxin 6 mediates protective function of astrocytes in Aβ proteostasis.

Pankiewicz Joanna E JE Diaz Jenny R JR Martá-Ariza Mitchell M Lizińczyk Anita M AM Franco Leor A LA Sadowski Martin J MJ

Molecular neurodegeneration 20200909 1

<h4>Background</h4>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<sub>2</sub>) activities involved in repair of ...[more]

PMID: 32907613

Similar Datasets

Project description:Ischemia-like conditions reflect almost the entire spectrum of events that occur during cerebral ischemia, including the induction of oxidative stress, Ca2+ overload, glutamate excitotoxicity, and activation of necrosis and apoptosis in brain cells. Mechanisms for the protective effects of the antioxidant enzyme peroxiredoxin-6 (Prx-6) on hippocampal cells during oxygen-glucose deprivation/reoxygenation (OGD/R) were investigated. Using the methods of fluorescence microscopy, inhibitory analysis, vitality tests and PCR, it was shown that 24-h incubation of mixed hippocampal cell cultures with Prx-6 does not affect the generation of a reversible phase of a OGD-induced rise in Ca2+ ions in cytosol ([Ca2+]i), but inhibits a global increase in [Ca2+]i in astrocytes completely and in neurons by 70%. In addition, after 40 min of OGD, cell necrosis is suppressed, especially in the astrocyte population. This effect is associated with the complex action of Prx-6 on neuroglial networks. As an antioxidant, Prx-6 has a more pronounced and astrocyte-directed effect, compared to the exogenous antioxidant vitamin E (Vit E). Prx-6 inhibits ROS production in mitochondria by increasing the antioxidant capacity of cells and altering the expression of genes encoding redox status proteins. Due to the close bond between [Ca2+]i and intracellular ROS, this effect of Prx-6 is one of its protective mechanisms. Moreover, Prx-6 effectively suppresses not only necrosis, but also apoptosis during OGD and reoxygenation. Incubation with Prx-6 leads to activation of the basic expression of genes encoding protective kinases-PI3K, CaMKII, PKC, anti-apoptotic proteins-Stat3 and Bcl-2, while inhibiting the expression of signaling kinases and factors involved in apoptosis activation-Ikk, Src, NF-κb, Caspase-3, p53, Fas, etc. This effect on the basic expression of the genome leads to the cell preconditions, which is expressed in the inhibition of caspase-3 during OGD/reoxygenation. A significant effect of Prx-6 is directed on suppression of the level of pro-inflammatory cytokine IL-1β and factor TNFα, as well as genes encoding NMDA- and kainate receptor subunits, which was established for the first time for this antioxidant enzyme. The protective effect of Prx-6 is due to its antioxidant properties, since mutant Prx-6 (mutPrx-6, Prx6-C47S) leads to polar opposite effects, contributing to oxidative stress, activation of apoptosis and cell death through receptor action on TLR4.

Project description:OBJECTIVES:White-matter injury after surgery is common in neonates with cerebral immaturity secondary to in utero hypoxia. Astrocytes play a central role in brain protection; however, the reaction of astrocytes to hypothermic circulatory arrest (HCA) remains unknown. We investigated the role of astrocytes in white-matter injury after HCA and determined the effects of preoperative hypoxia on this role, using a novel mouse model. METHODS:Mice were exposed to hypoxia from days 3 to 11, which is equivalent to the third trimester in humans (prehypoxia, n = 49). Brain slices were transferred to a chamber perfused by cerebrospinal fluid. Oxygen-glucose deprivation (OGD) was performed to simulate ischemia-reperfusion/reoxygenation resulting from circulatory arrest under hypothermia. Astrocyte reactions were compared with preoperative normoxia (prenormoxia; n = 45). RESULTS:We observed astrocyte activation after 25°C ischemia-reperfusion/reoxygenation in prenormoxia (P < .01). Astrocyte number after OGD correlated with caspase-3(+) cells (rho = .77, P = .001), confirming that astrogliosis is an important response after HCA. At 3 hours after OGD, astrocytes in prenormoxia had already proliferated and become activated (P < .05). Conversely, astrocytes that developed under hypoxia did not display these responses. At 20 hours after ischemia-reperfusion/reoxygenation, astrogliosis was not observed in prehypoxia, demonstrating that hypoxia altered the response of astrocytes to insult. In contrast to prenormoxia, caspase-3(+) cells in prehypoxia increased after ischemia reperfusion/reoxygenation, compared with control (P < .01). Caspase-3(+) cells were more common with prehypoxia than with prenormoxia (P < .001), suggesting that lack of astrogliosis permits increased white-matter injury. CONCLUSIONS:Preoperative hypoxia alters the neuroprotective function of astrocytes. Restoring this function before surgery may be a therapeutic option to reduce postoperative white-matter injury in the immature brain.

Dataset Information

Peroxiredoxin 6 mediates protective function of astrocytes in A? proteostasis.

Publications

Peroxiredoxin 6 mediates protective function of astrocytes in Aβ proteostasis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets