Elevated 24-hydroxycholesterol levels counteract okadaic acid-induced tau hyperphosphorylation and neuronal morphology impairment
Multiple findings underline a link between altered brain cholesterol metabolism and Alzheimer's disease (AD) pathogenesis. Physiologically, excess brain cholesterol is mainly converted into 24-hydroxycholesterol (24-OHC) by the neuron-specific enzyme CYP46A1. Of note, we previously observed in...
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Elsevier
2025-10-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125002451 |
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| author | Serena Giannelli Francesca Eroli Raúl Loera-Valencia Valerio Leoni Maria Latorre-Leal Gabriella Testa Erica Staurenghi Barbara Sottero Paola Gamba Silvia Maioli Gabriella Leonarduzzi |
| author_facet | Serena Giannelli Francesca Eroli Raúl Loera-Valencia Valerio Leoni Maria Latorre-Leal Gabriella Testa Erica Staurenghi Barbara Sottero Paola Gamba Silvia Maioli Gabriella Leonarduzzi |
| author_sort | Serena Giannelli |
| collection | DOAJ |
| description | Multiple findings underline a link between altered brain cholesterol metabolism and Alzheimer's disease (AD) pathogenesis. Physiologically, excess brain cholesterol is mainly converted into 24-hydroxycholesterol (24-OHC) by the neuron-specific enzyme CYP46A1. Of note, we previously observed in autopsy specimens from human AD brains that 24-OHC and, in parallel, CYP46A1 expression decrease at advanced stages, suggesting a possible cause-effect between these reductions and AD progression. In the present study, we aimed to investigate whether maintaining high levels of 24-OHC, by its exogenous administration or CYP46A1 overexpression, can counteract tau hyperphosphorylation and accumulation of prefibrillar tau oligomers. To create an AD-like in vitro model exhibiting tauopathy, we utilized okadaic acid (OKA), a chemical compound that induces tau hyperphosphorylation. Our data show that in 24-OHC-treated primary neurons derived from wild type mice and in neurons from CYP46A1 overexpressing mice (CYP46Tg) elevated oxysterol levels effectively prevented tau hyperphosphorylation and oligomerization. Furthermore, the dendritic arborization decrease induced by OKA was prevented, maintaining the organization and stability of the neuronal cytoskeleton. While hypothesized underlying molecular mechanisms (GSK3β, CDK5, ERK1/2, and PP2A) seem not to be involved, the protective effect of 24-OHC remains evident. The data highlight the positive effects of 24-OHC and the need to prevent its reduction in the brain. This can be achieved either through the exogenous administration of 24-OHC using suitable technologies or by maintaining elevated levels and the activity of the enzyme CYP46A1. These therapeutic approaches could be useful to prevent or slow AD progression. |
| format | Article |
| id | doaj-art-d34a301880ee40aabe2f5fca96e57fac |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-d34a301880ee40aabe2f5fca96e57fac2025-08-20T03:51:25ZengElsevierNeurobiology of Disease1095-953X2025-10-0121410702910.1016/j.nbd.2025.107029Elevated 24-hydroxycholesterol levels counteract okadaic acid-induced tau hyperphosphorylation and neuronal morphology impairmentSerena Giannelli0Francesca Eroli1Raúl Loera-Valencia2Valerio Leoni3Maria Latorre-Leal4Gabriella Testa5Erica Staurenghi6Barbara Sottero7Paola Gamba8Silvia Maioli9Gabriella Leonarduzzi10Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, Orbassano, Turin, Italy; Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, Stockholm, SwedenDepartment of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, Stockholm, SwedenDepartment of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden; Tecnologico de Monterrey, School of Medicine and Health Sciences, Chihuahua, MexicoLaboratory of Clinical Pathology, Hospital Pio XI of Desio, ASST-Brianza and Department of Medicine and Surgery, University of Milano-Bicocca, Desio, ItalyDepartment of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, Stockholm, SwedenDepartment of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, Orbassano, Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, Orbassano, Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, Orbassano, Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, Orbassano, Turin, ItalyDepartment of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden; Corresponding authors.Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, Orbassano, Turin, Italy; Corresponding authors.Multiple findings underline a link between altered brain cholesterol metabolism and Alzheimer's disease (AD) pathogenesis. Physiologically, excess brain cholesterol is mainly converted into 24-hydroxycholesterol (24-OHC) by the neuron-specific enzyme CYP46A1. Of note, we previously observed in autopsy specimens from human AD brains that 24-OHC and, in parallel, CYP46A1 expression decrease at advanced stages, suggesting a possible cause-effect between these reductions and AD progression. In the present study, we aimed to investigate whether maintaining high levels of 24-OHC, by its exogenous administration or CYP46A1 overexpression, can counteract tau hyperphosphorylation and accumulation of prefibrillar tau oligomers. To create an AD-like in vitro model exhibiting tauopathy, we utilized okadaic acid (OKA), a chemical compound that induces tau hyperphosphorylation. Our data show that in 24-OHC-treated primary neurons derived from wild type mice and in neurons from CYP46A1 overexpressing mice (CYP46Tg) elevated oxysterol levels effectively prevented tau hyperphosphorylation and oligomerization. Furthermore, the dendritic arborization decrease induced by OKA was prevented, maintaining the organization and stability of the neuronal cytoskeleton. While hypothesized underlying molecular mechanisms (GSK3β, CDK5, ERK1/2, and PP2A) seem not to be involved, the protective effect of 24-OHC remains evident. The data highlight the positive effects of 24-OHC and the need to prevent its reduction in the brain. This can be achieved either through the exogenous administration of 24-OHC using suitable technologies or by maintaining elevated levels and the activity of the enzyme CYP46A1. These therapeutic approaches could be useful to prevent or slow AD progression.http://www.sciencedirect.com/science/article/pii/S096999612500245124-hydroxycholesterolCYP46A1Tau hyperphosphorylationTau oligomersDendritic arborizationAlzheimer's disease |
| spellingShingle | Serena Giannelli Francesca Eroli Raúl Loera-Valencia Valerio Leoni Maria Latorre-Leal Gabriella Testa Erica Staurenghi Barbara Sottero Paola Gamba Silvia Maioli Gabriella Leonarduzzi Elevated 24-hydroxycholesterol levels counteract okadaic acid-induced tau hyperphosphorylation and neuronal morphology impairment Neurobiology of Disease 24-hydroxycholesterol CYP46A1 Tau hyperphosphorylation Tau oligomers Dendritic arborization Alzheimer's disease |
| title | Elevated 24-hydroxycholesterol levels counteract okadaic acid-induced tau hyperphosphorylation and neuronal morphology impairment |
| title_full | Elevated 24-hydroxycholesterol levels counteract okadaic acid-induced tau hyperphosphorylation and neuronal morphology impairment |
| title_fullStr | Elevated 24-hydroxycholesterol levels counteract okadaic acid-induced tau hyperphosphorylation and neuronal morphology impairment |
| title_full_unstemmed | Elevated 24-hydroxycholesterol levels counteract okadaic acid-induced tau hyperphosphorylation and neuronal morphology impairment |
| title_short | Elevated 24-hydroxycholesterol levels counteract okadaic acid-induced tau hyperphosphorylation and neuronal morphology impairment |
| title_sort | elevated 24 hydroxycholesterol levels counteract okadaic acid induced tau hyperphosphorylation and neuronal morphology impairment |
| topic | 24-hydroxycholesterol CYP46A1 Tau hyperphosphorylation Tau oligomers Dendritic arborization Alzheimer's disease |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125002451 |
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