APOEε4 alters ApoE and Fabp7 in frontal cortex white matter in prodromal Alzheimer's disease
Abstract The ApoE ε4 allele (APOEε4) is a major genetic risk factor for sporadic Alzheimer's disease (AD) and is linked to demyelination and cognitive decline. However, its effects on the lipid transporters apolipoprotein E (ApoE) and fatty acid-binding protein 7 (Fabp7), which are crucial for...
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2025-01-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | https://doi.org/10.1186/s12974-025-03349-y |
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| author | Marta Moreno-Rodriguez Sylvia E. Perez Michael Malek-Ahmadi Elliott J. Mufson |
| author_facet | Marta Moreno-Rodriguez Sylvia E. Perez Michael Malek-Ahmadi Elliott J. Mufson |
| author_sort | Marta Moreno-Rodriguez |
| collection | DOAJ |
| description | Abstract The ApoE ε4 allele (APOEε4) is a major genetic risk factor for sporadic Alzheimer's disease (AD) and is linked to demyelination and cognitive decline. However, its effects on the lipid transporters apolipoprotein E (ApoE) and fatty acid-binding protein 7 (Fabp7), which are crucial for the maintenance of myelin in white matter (WM) during the progression of AD remain underexplored. To evaluate the effects of APOEε4 on ApoE, Fabp7 and myelin in the WM of the frontal cortex (FC), we examined individuals carrying one ε4 allele that came to autopsy with a premortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI) and mild to moderate AD compared with non-carrier counterparts. ApoE, Fabp7 and Olig2 immunostaining was used to visualize cells, whereas myelin basic protein (MBP) immunocytochemistry and luxol fast blue (LFB) histochemistry of myelin in the WM of the FC were combined with quantitative morphometry. We observed increased numbers of ApoE-positive astrocytes in the WM of both NCI and MCI APOEε4 carriers compared with non-carriers, whereas Fabp7-positive cells were elevated only in AD. Conversely, Olig2 cell counts and MBP immunostaining decreased in MCI APOEε4 carriers compared to non-carriers, while LFB levels were higher in NCI APOEε4 carriers compared to non-carriers. Although no correlations were found between ApoE, Fabp7, and cognitive status, LFB measurements were positively correlated with perceptual speed, global cognition, and visuospatial scores in APOEε4 carriers across clinical groups. The present findings suggest that the ε4 allele compromises FC myelin homeostasis by disrupting the lipid transporters ApoE, Fabp7 and myelination early in the onset of AD. These data support targeting cellular components related to WM integrity as possible treatments for AD. |
| format | Article |
| id | doaj-art-cf68d5757bf543129de57e70a09008f1 |
| institution | Kabale University |
| issn | 1742-2094 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj-art-cf68d5757bf543129de57e70a09008f12025-02-02T12:35:04ZengBMCJournal of Neuroinflammation1742-20942025-01-0122111710.1186/s12974-025-03349-yAPOEε4 alters ApoE and Fabp7 in frontal cortex white matter in prodromal Alzheimer's diseaseMarta Moreno-Rodriguez0Sylvia E. Perez1Michael Malek-Ahmadi2Elliott J. Mufson3Department of Translational Neuroscience, Barrow Neurological InstituteDepartment of Translational Neuroscience, Barrow Neurological InstituteBanner Alzheimer’s InstituteDepartment of Translational Neuroscience, Barrow Neurological InstituteAbstract The ApoE ε4 allele (APOEε4) is a major genetic risk factor for sporadic Alzheimer's disease (AD) and is linked to demyelination and cognitive decline. However, its effects on the lipid transporters apolipoprotein E (ApoE) and fatty acid-binding protein 7 (Fabp7), which are crucial for the maintenance of myelin in white matter (WM) during the progression of AD remain underexplored. To evaluate the effects of APOEε4 on ApoE, Fabp7 and myelin in the WM of the frontal cortex (FC), we examined individuals carrying one ε4 allele that came to autopsy with a premortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI) and mild to moderate AD compared with non-carrier counterparts. ApoE, Fabp7 and Olig2 immunostaining was used to visualize cells, whereas myelin basic protein (MBP) immunocytochemistry and luxol fast blue (LFB) histochemistry of myelin in the WM of the FC were combined with quantitative morphometry. We observed increased numbers of ApoE-positive astrocytes in the WM of both NCI and MCI APOEε4 carriers compared with non-carriers, whereas Fabp7-positive cells were elevated only in AD. Conversely, Olig2 cell counts and MBP immunostaining decreased in MCI APOEε4 carriers compared to non-carriers, while LFB levels were higher in NCI APOEε4 carriers compared to non-carriers. Although no correlations were found between ApoE, Fabp7, and cognitive status, LFB measurements were positively correlated with perceptual speed, global cognition, and visuospatial scores in APOEε4 carriers across clinical groups. The present findings suggest that the ε4 allele compromises FC myelin homeostasis by disrupting the lipid transporters ApoE, Fabp7 and myelination early in the onset of AD. These data support targeting cellular components related to WM integrity as possible treatments for AD.https://doi.org/10.1186/s12974-025-03349-yAPOEε4Fabp7AstrocytesWhite matterAlzheimer's diseaseMild cognitive impairment |
| spellingShingle | Marta Moreno-Rodriguez Sylvia E. Perez Michael Malek-Ahmadi Elliott J. Mufson APOEε4 alters ApoE and Fabp7 in frontal cortex white matter in prodromal Alzheimer's disease Journal of Neuroinflammation APOEε4 Fabp7 Astrocytes White matter Alzheimer's disease Mild cognitive impairment |
| title | APOEε4 alters ApoE and Fabp7 in frontal cortex white matter in prodromal Alzheimer's disease |
| title_full | APOEε4 alters ApoE and Fabp7 in frontal cortex white matter in prodromal Alzheimer's disease |
| title_fullStr | APOEε4 alters ApoE and Fabp7 in frontal cortex white matter in prodromal Alzheimer's disease |
| title_full_unstemmed | APOEε4 alters ApoE and Fabp7 in frontal cortex white matter in prodromal Alzheimer's disease |
| title_short | APOEε4 alters ApoE and Fabp7 in frontal cortex white matter in prodromal Alzheimer's disease |
| title_sort | apoeε4 alters apoe and fabp7 in frontal cortex white matter in prodromal alzheimer s disease |
| topic | APOEε4 Fabp7 Astrocytes White matter Alzheimer's disease Mild cognitive impairment |
| url | https://doi.org/10.1186/s12974-025-03349-y |
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