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The Controversial Role of 24-S-Hydroxycholesterol in Alzheimer’s Disease

Gamba, Paola, Giannelli, Serena, Staurenghi, Erica, Testa, Gabriella, Sottero, Barbara, Biasi, Fiorella, Poli, Giuseppe, Leonarduzzi, Gabriella·2021·Antioxidants
DOI 10.3390/antiox10050740
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Abstract

The development of Alzheimer’s disease (AD) is influenced by several events, among which the dysregulation of cholesterol metabolism in the brain plays a major role. Maintenance of brain cholesterol homeostasis is essential for neuronal functioning and brain development. To maintain the steady-state level, excess brain cholesterol is converted into the more hydrophilic metabolite 24-S-hydroxycholesterol (24-OHC), also called cerebrosterol, by the neuron-specific enzyme CYP46A1. A growing bulk of evidence suggests that cholesterol oxidation products, named oxysterols, are the link connecting altered cholesterol metabolism to AD. It has been shown that the levels of some oxysterols, including 27-hydroxycholesterol, 7β-hydroxycholesterol and 7-ketocholesterol, significantly increase in AD brains contributing to disease progression. In contrast, 24-OHC levels decrease, likely due to neuronal loss. Among the different brain oxysterols, 24-OHC is certainly the one whose role is most controversial. It is the dominant oxysterol in the brain and evidence shows that it represents a signaling molecule of great importance for brain function. However, numerous studies highlighted the potential role of 24-OHC in favoring AD development, since it promotes neuroinflammation, amyloid β (Aβ) peptide production, oxidative stress and cell death. In parallel, 24-OHC has been shown to exert several beneficial effects against AD progression, such as preventing tau hyperphosphorylation and Aβ production. In this review we focus on the current knowledge of the controversial role of 24-OHC in AD pathogenesis, reporting a detailed overview of the findings about its levels in different AD biological samples and its noxious or neuroprotective effects in the brain. Given the relevant role of 24-OHC in AD pathophysiology, its targeting could be useful for disease prevention or slowing down its progression.

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Metadata

Authors
Gamba, P., Giannelli, S., Staurenghi, E., Testa, G., Sottero, B., Biasi, F., Poli, G., & Leonarduzzi, G.
Affiliations
Department of Clinical and Biological Sciences, University of Turin, 10043 Turin, Italy
ORCID
Venue
Antioxidants
Publisher
MDPI AG
Published
2021-05-07
Volume
10
Issue
5
Pages
740
ISSN
2076-3921
DOI
10.3390/antiox10050740
Cited by
70
References
10
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
Università degli Studi di Torino (GAMP_RILO_20_01 and LEOG_RILO_20_01)

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