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.
Prion diseases or prionoses are a group of rapidly progressing and invariably fatal neurodegenerative diseases. The pathogenesis of prionoses is associated with self-replication and connectomal spread of PrPSc, a disease specific conformer of the prion protein. Microglia undergo activation early in the course of prion pathogenesis and exert opposing roles in PrPSc mediated neurodegeneration. While clearance of PrPSc and apoptotic neurons have disease-limiting effect, microglia-driven neuroinflammation bears deleterious consequences to neuronal networks. Apolipoprotein (apo) E is a lipid transporting protein with pleiotropic functions, which include controlling of the phagocytic and inflammatory characteristics of activated microglia in neurodegenerative diseases. Despite the significance of microglia in prion pathogenesis, the role of apoE in prionoses has not been established. We showed here that infection of wild type mice with 22L mouse adapted scrapie strain is associated with significant increase in the total brain apoE protein and mRNA levels and also with a conspicuous cell-type shift in the apoE expression. There is reduced expression of apoE in activated astrocytes and marked upregulation of apoE expression by activated microglia. We also showed apoE ablation exaggerates PrPSc mediated neurodegeneration. Apoe−/− mice have shorter disease incubation period, increased load of spongiform lesion, pronounced neuronal loss, and exaggerated astro and microgliosis. Astrocytes of Apoe−/− mice display salient upregulation of transcriptomic markers defining A1 neurotoxic astrocytes while microglia show upregulation of transcriptomic markers characteristic for microglial neurodegenerative phenotype. There is impaired clearance of PrPSc and dying neurons by microglia in Apoe−/− mice along with increased level of proinflammatory cytokines. Our work indicates that apoE absence renders clearance of PrPSc and dying neurons by microglia inefficient, while the excess of neuronal debris promotes microglial neurodegenerative phenotype aggravating the vicious cycle of neuronal death and neuroinflammation.
BackgroundIn Alzheimer’s disease (AD) neurons, which accumulate hyperphosphorylated tau (p‐tau) are associated with neurodegenerative phenotype microglia (MGnD) and A1 neurotoxic astrocytes. MGnD display reduced ability to phagocytose p‐tau aggregates and neuronal remnants, while their pro‐inflammatory character furthers p‐tau accumulation and neuronal demise. Likewise, A1 astrocytes lose their neuron‐supporting function and promote neurodegeneration. Importantly, MGnD and A1 astrocytes reciprocally stimulate their pathological phenotypes. Factors protecting astrocytes form A1 phenotype transformation are unknown. In this work we explored the role of peroxiredoxin (PRDX) 6 in tau mediated neurodegeneration. PRDX6 is an enzymatic protein which in the CNS is unique to astrocytes. It possesses independent glutathione peroxidase and phospholipase 2 enzymatic activities, which confer ability to repair oxidatively damaged cell membranes and cell‐to‐cell signaling.Method MAPT P301S mutant mice (PS19/Prdx6 +/+) were once crossed to Prdx6 ‐/‐ mice and mice homozygous for the knock‐in of the Prdx6 129X1/SvJ allele overexpressing wild‐type PRDX6 to generate novel PS19/Prdx6 +/‐ and PS19/Prdx6 Tg lines, respectively. Eight weeks old PS19/Prdx6 +/‐, PS19/Prdx6 +/+, and PS19/Prdx6 Tg animals show 0.4:1:2 ratio of Prdx6 brain mRNA level, while levels of hTau and Gfap mRNA remain unchanged. Male mice were neuropathologically characterized at the age of 9.5 months.Result PS19/Prdx6 +/‐ mice feature increased hippocampal atrophy and ventricular enlargement and greater p‐tau accumulation compared to PS19/Prdx6 +/+ mice. Contrariwise, PS19/Prdx6 Tg animals show attenuated brain atrophy and p‐tau accumulation. The GFAP+ load used as a marker of global astrocytic activation and the C3+/GFAP+ ratio, used as a surrogate A1 phenotype marker, vary inversely with the Prdx6 gene dose. Likewise, the load of IBA1+ microglia vary inversely with the Prdx6 gene dose, while the CD68+/IBA1+ index, which determines relative microglia phagocytic activity, directly correlates with the Prdx6 expression.ConclusionExacerbation of the pathological phenotype in PS19/Prdx6 +/‐ mice reveals a neuroprotective effect of PRDX6 in tau mediated neurodegeneration, while attenuation of pathology in PS19/Prdx6 Tg mice suggests a merit of therapeutic PRDX6 upregulation. PRDX6 endows astrocytes with resistance to A1 phenotype transition. Astrocytic PRDX6 also reprograms microglia by downregulating their global activation level and selectively promoting phagocytic properties. Comparative analysis of astrocytic and microglia transcriptomic markers across PS19/Prdx6 +/‐, PS19/Prdx6 +/+, and PS19/Prdx6 Tg genotypes is underway.
BackgroundBoth Alzheimer’s disease and prionoses are neurogenerative disorders, which involve misfolded protein deposition and transition of homeostatic microglia to their neurodegenerative phenotype. In prionoses, accumulation of toxic PrPSc protein constitutes the culprit of pathogenesis. Neurodegenerative phenotype microglia (MGnD) appear early in the course of disease and play opposing roles in PrPSc mediated neurodegeneration. Whilst clearance of PrPSc has a disease‐limiting effect, MGnD‐driven neuroinflammation is deleterious to neurons. Apolipoprotein (apo) E is a pleiotropic protein, which controls MGnD phagocytic and inflammatory characteristics. Despite prominent role of microglia in prionoses, involvement of apoE in their pathogenesis has not been established.MethodWild type (WT) and Apoe‐/‐ mice, both on the B6 background, were inoculated with 22L mouse adapted scrapie strain or normal brain homogenate. Neuropathological and biochemical analyses were performed 15 and 23 weeks post inoculation (WPI) on asymptomatic and overly symptomatic animals, respectively. NanoStringTM analysis of microglia and astrocytic transcriptomic markers was performed at 23WPI.ResultPrion infection of WT mice upregulates total brain apoE level and effects cell‐type shift in the apoE expression, downregulating astrocytic apoE while increasing microglial apoE 24‐folds. 22L Apoe‐/‐ mice have significantly shorter disease incubation period, higher load of spongiform changes, and increased total brain PrP and PrPSc levels compared to 22LWT mice. In 22L Apoe ‐/‐ mice astro and micro gliosis appears earlier and is more robust compared to 22LWT mice. Transcriptomic analysis shows significantly higher level of PAN and A1, but not A2 astrocytic markers and MGnD markers in 22L Apoe ‐/‐ mice compared to 22LWT animals. Microglia in 22L Apoe ‐/‐ mice feature impaired neuronal phagocytosis and produce increased level of pro‐inflammatory interleukins and cytokines. 22L Apoe ‐/‐ mice show higher neuronal loss and greater tempo of neuronal degeneration than 22LWT mice.ConclusionOur results indicate the net effect of apoE in prion pathogenesis is protective. ApoE facilitates clearance of PrPSc and dying neurons by microglia, which becomes ineffective in the absence of apoE. Remnants of disintegrating neurons promote MGnD phenotype transition and inflammatory cascade propagating the vicious cycle of neuronal death and neuroinflammation. Our data also indicate homeostatic microglia transit to the MGnD even if they do not express apoE.
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