Changes in brain oxysterols at different stages of Alzheimer's disease: Their involvement in neuroinflammation
Alzheimer's disease (AD) is a gradually debilitating disease that leads to dementia. The molecular mechanisms underlying AD are still not clear, and at present no reliable biomarkers are available for the early diagnosis. In the last several years, together with oxidative stress and neuroinflam...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2016-12-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231716300945 |
| _version_ | 1818483769580978176 |
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| author | Gabriella Testa Erica Staurenghi Chiara Zerbinati Simona Gargiulo Luigi Iuliano Giorgio Giaccone Fausto Fantò Giuseppe Poli Gabriella Leonarduzzi Paola Gamba |
| author_facet | Gabriella Testa Erica Staurenghi Chiara Zerbinati Simona Gargiulo Luigi Iuliano Giorgio Giaccone Fausto Fantò Giuseppe Poli Gabriella Leonarduzzi Paola Gamba |
| author_sort | Gabriella Testa |
| collection | DOAJ |
| description | Alzheimer's disease (AD) is a gradually debilitating disease that leads to dementia. The molecular mechanisms underlying AD are still not clear, and at present no reliable biomarkers are available for the early diagnosis. In the last several years, together with oxidative stress and neuroinflammation, altered cholesterol metabolism in the brain has become increasingly implicated in AD progression. A significant body of evidence indicates that oxidized cholesterol, in the form of oxysterols, is one of the main triggers of AD. The oxysterols potentially most closely involved in the pathogenesis of AD are 24-hydroxycholesterol and 27-hydroxycholesterol, respectively deriving from cholesterol oxidation by the enzymes CYP46A1 and CYP27A1. However, the possible involvement of oxysterols resulting from cholesterol autooxidation, including 7-ketocholesterol and 7β-hydroxycholesterol, is now emerging. In a systematic analysis of oxysterols in post-mortem human AD brains, classified by the Braak staging system of neurofibrillary pathology, alongside the two oxysterols of enzymatic origin, a variety of oxysterols deriving from cholesterol autoxidation were identified; these included 7-ketocholesterol, 7α-hydroxycholesterol, 4β-hydroxycholesterol, 5α,6α-epoxycholesterol, and 5β,6β-epoxycholesterol. Their levels were quantified and compared across the disease stages. Some inflammatory mediators, and the proteolytic enzyme matrix metalloprotease-9, were also found to be enhanced in the brains, depending on disease progression. This highlights the pathogenic association between the trends of inflammatory molecules and oxysterol levels during the evolution of AD. Conversely, sirtuin 1, an enzyme that regulates several pathways involved in the anti-inflammatory response, was reduced markedly with the progression of AD, supporting the hypothesis that the loss of sirtuin 1 might play a key role in AD. Taken together, these results strongly support the association between changes in oxysterol levels and AD progression. |
| first_indexed | 2024-12-10T15:46:20Z |
| format | Article |
| id | doaj.art-062e1ca7b69649ba9efec1670064ba74 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-10T15:46:20Z |
| publishDate | 2016-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-062e1ca7b69649ba9efec1670064ba742022-12-22T01:42:56ZengElsevierRedox Biology2213-23172016-12-0110C243310.1016/j.redox.2016.09.001Changes in brain oxysterols at different stages of Alzheimer's disease: Their involvement in neuroinflammationGabriella Testa0Erica Staurenghi1Chiara Zerbinati2Simona Gargiulo3Luigi Iuliano4Giorgio Giaccone5Fausto Fantò6Giuseppe Poli7Gabriella Leonarduzzi8Paola Gamba9Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, ItalyDepartment of Medico-Surgical Sciences and Biotechnology, Vascular Biology and Mass Spectrometry Laboratory, Sapienza University of Rome, Latina, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, ItalyDepartment of Medico-Surgical Sciences and Biotechnology, Vascular Biology and Mass Spectrometry Laboratory, Sapienza University of Rome, Latina, ItalyFoundation IRCCS Carlo Besta Institute of Neurology, Milan, ItalyGeriatric Division, A.O.U. San Luigi Gonzaga, Orbassano, Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, ItalyAlzheimer's disease (AD) is a gradually debilitating disease that leads to dementia. The molecular mechanisms underlying AD are still not clear, and at present no reliable biomarkers are available for the early diagnosis. In the last several years, together with oxidative stress and neuroinflammation, altered cholesterol metabolism in the brain has become increasingly implicated in AD progression. A significant body of evidence indicates that oxidized cholesterol, in the form of oxysterols, is one of the main triggers of AD. The oxysterols potentially most closely involved in the pathogenesis of AD are 24-hydroxycholesterol and 27-hydroxycholesterol, respectively deriving from cholesterol oxidation by the enzymes CYP46A1 and CYP27A1. However, the possible involvement of oxysterols resulting from cholesterol autooxidation, including 7-ketocholesterol and 7β-hydroxycholesterol, is now emerging. In a systematic analysis of oxysterols in post-mortem human AD brains, classified by the Braak staging system of neurofibrillary pathology, alongside the two oxysterols of enzymatic origin, a variety of oxysterols deriving from cholesterol autoxidation were identified; these included 7-ketocholesterol, 7α-hydroxycholesterol, 4β-hydroxycholesterol, 5α,6α-epoxycholesterol, and 5β,6β-epoxycholesterol. Their levels were quantified and compared across the disease stages. Some inflammatory mediators, and the proteolytic enzyme matrix metalloprotease-9, were also found to be enhanced in the brains, depending on disease progression. This highlights the pathogenic association between the trends of inflammatory molecules and oxysterol levels during the evolution of AD. Conversely, sirtuin 1, an enzyme that regulates several pathways involved in the anti-inflammatory response, was reduced markedly with the progression of AD, supporting the hypothesis that the loss of sirtuin 1 might play a key role in AD. Taken together, these results strongly support the association between changes in oxysterol levels and AD progression.http://www.sciencedirect.com/science/article/pii/S2213231716300945Alzheimer's diseaseOxysterolsSirtuin-1InflammationCholesterol metabolism |
| spellingShingle | Gabriella Testa Erica Staurenghi Chiara Zerbinati Simona Gargiulo Luigi Iuliano Giorgio Giaccone Fausto Fantò Giuseppe Poli Gabriella Leonarduzzi Paola Gamba Changes in brain oxysterols at different stages of Alzheimer's disease: Their involvement in neuroinflammation Redox Biology Alzheimer's disease Oxysterols Sirtuin-1 Inflammation Cholesterol metabolism |
| title | Changes in brain oxysterols at different stages of Alzheimer's disease: Their involvement in neuroinflammation |
| title_full | Changes in brain oxysterols at different stages of Alzheimer's disease: Their involvement in neuroinflammation |
| title_fullStr | Changes in brain oxysterols at different stages of Alzheimer's disease: Their involvement in neuroinflammation |
| title_full_unstemmed | Changes in brain oxysterols at different stages of Alzheimer's disease: Their involvement in neuroinflammation |
| title_short | Changes in brain oxysterols at different stages of Alzheimer's disease: Their involvement in neuroinflammation |
| title_sort | changes in brain oxysterols at different stages of alzheimer s disease their involvement in neuroinflammation |
| topic | Alzheimer's disease Oxysterols Sirtuin-1 Inflammation Cholesterol metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S2213231716300945 |
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