Moreno-Rodriguez Marta, Perez Sylvia E, Malek-Ahmadi Michael, Mufson Elliott J
Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, 85013, USA.
Banner Alzheimer's Institute, Phoenix, AZ, 85006, USA.
J Neuroinflammation. 2025 Jan 30;22(1):25. doi: 10.1186/s12974-025-03349-y.
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.
载脂蛋白Eε4等位基因（APOEε4）是散发性阿尔茨海默病（AD）的主要遗传风险因素，与脱髓鞘和认知衰退有关。然而，在AD进展过程中，其对脂质转运蛋白载脂蛋白E（ApoE）和脂肪酸结合蛋白7（Fabp7）的影响仍未得到充分研究，而这两种蛋白对维持白质（WM）中的髓鞘至关重要。为了评估APOEε4对额叶皮质（FC）白质中ApoE、Fabp7和髓鞘的影响，我们检查了携带一个ε4等位基因且生前临床诊断为无认知障碍（NCI）、轻度认知障碍（MCI）和轻度至中度AD的个体，并与非携带者进行比较。使用ApoE、Fabp7和少突胶质细胞转录因子2（Olig2）免疫染色来观察细胞，而FC白质中髓鞘碱性蛋白（MBP）免疫细胞化学和髓鞘蓝紫染色（LFB）组织化学则与定量形态测量相结合。我们观察到，与非携带者相比，NCI和MCI的APOEε4携带者白质中ApoE阳性星形胶质细胞数量增加，而Fabp7阳性细胞仅在AD中升高。相反，与非携带者相比，MCI的APOEε4携带者中Olig2细胞计数和MBP免疫染色减少，而与非携带者相比，NCI的APOEε4携带者中LFB水平更高。尽管在ApoE、Fabp7和认知状态之间未发现相关性，但在各临床组的APOEε4携带者中，LFB测量值与感知速度、整体认知和视觉空间得分呈正相关。目前的研究结果表明，ε4等位基因通过在AD发病早期破坏脂质转运蛋白ApoE、Fabp7和髓鞘形成，损害了FC髓鞘稳态。这些数据支持将与WM完整性相关的细胞成分作为AD的可能治疗靶点。
