Loss of biliverdin reductase-A favors Tau hyper-phosphorylation in Alzheimer's disease.
Neurobiol Dis
; 125: 176-189, 2019 05.
Article
em En
| MEDLINE
| ID: mdl-30738142
ABSTRACT
Hyper-active GSK-3ß favors Tau phosphorylation during the progression of Alzheimer's disease (AD). Akt is one of the main kinases inhibiting GSK-3ß and its activation occurs in response to neurotoxic stimuli including, i.e., oxidative stress. Biliverdin reductase-A (BVR-A) is a scaffold protein favoring the Akt-mediated inhibition of GSK-3ß. Reduced BVR-A levels along with increased oxidative stress were observed early in the hippocampus of 3xTg-AD mice (at 6â¯months), thus suggesting that loss of BVR-A could be a limiting factor in the oxidative stress-induced Akt-mediated inhibition of GSK-3ß in AD. We evaluated changes of BVR-A, Akt, GSK-3ß, oxidative stress and Tau phosphorylation levels (a) in brain from young (6-months) and old (12-months) 3xTg-AD mice; and (b) in post-mortem inferior parietal lobule (IPL) samples from amnestic mild cognitive impairment (MCI), from AD and from age-matched controls. Furthermore, similar analyses were performed in vitro in cells lacking BVR-A and treated with H2O2. Reduced BVR-A levels along with (a) increased oxidative stress; (b) reduced GSK-3ß inhibition; and (c) increased Tau Ser404 phosphorylation (target of GSK-3ß activity) without changes of Akt activation in young mice, were observed. Similar findings were obtained in MCI, consistent with the notion that this is a molecular mechanism disrupted in humans. Interestingly, cells lacking BVR-A and treated with H2O2 showed reduced GSK-3ß inhibition and increased Tau Ser404 phosphorylation, which resulted from a defect of Akt and GSK-3ß physical interaction. Reduced levels of Akt/GSK-3ß complex were confirmed in both young 3xTg-AD and MCI brain. We demonstrated that loss of BVR-A impairs the neuroprotective Akt-mediated inhibition of GSK-3ß in response to oxidative stress, thus contributing to Tau hyper-phosphorylation in early stage AD. Such changes potential provide promising therapeutic targets for this devastating disorder.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas tau
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Estresse Oxidativo
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Oxirredutases atuantes sobre Doadores de Grupo CH-CH
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Doença de Alzheimer
Limite:
Aged80
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Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Neurobiol Dis
Assunto da revista:
NEUROLOGIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Itália