CICS-UBI-Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal.
Department of Neurobiology, School of Biology/Chemistry, University of Osnabrück, 49074 Osnabrück, Germany.
Int J Mol Sci. 2020 Sep 17;21(18):6813. doi: 10.3390/ijms21186813.
Accumulation of amyloid-beta (Aβ) in the brain is thought to derive from the impairment of Aβ clearance mechanisms rather than from its overproduction, which consequently contributes to the development of Alzheimer's disease. The choroid plexus epithelial cells constitute an important clearance route for Aβ, either by facilitating its transport from the cerebrospinal fluid to the blood, or by synthesizing and secreting various proteins involved in Aβ degradation. Impaired choroid plexus synthesis, secretion, and transport of these Aβ-metabolizing enzymes have been therefore associated with the disruption of Aβ homeostasis and amyloid load. Factors such as aging, female gender, and circadian rhythm disturbances are related to the decline of choroid plexus functions that may be involved in the modulation of Aβ-clearance mechanisms. In this study, we investigated the impact of age, sex hormones, and circadian rhythm on the expression of Aβ scavengers such as apolipoprotein J, gelsolin, and transthyretin at the rat choroid plexus. Our results demonstrated that mRNA expression and both intracellular and secreted protein levels of the studied Aβ scavengers are age-, sex-, and circadian-dependent. These data suggest that the Aβ-degradation and clearance pathways at the choroid plexus, mediated by the presence of Aβ scavengers, might be compromised as a consequence of aging and circadian disturbances. These are important findings that enhance the understanding of Aβ-clearance-regulating mechanisms at the blood-cerebrospinal fluid barrier.
脑内淀粉样蛋白-β（Aβ）的积累被认为源于 Aβ 清除机制的损伤，而非其过度产生，这继而导致了阿尔茨海默病的发生。脉络丛上皮细胞构成了 Aβ 的一个重要清除途径，通过促进其从脑脊液向血液的转运，或通过合成和分泌各种参与 Aβ 降解的蛋白质。因此，脉络丛合成、分泌和转运这些 Aβ 代谢酶的功能受损与 Aβ 动态平衡和淀粉样负荷的破坏有关。衰老、女性性别和昼夜节律紊乱等因素与脉络丛功能下降有关，而这些功能可能参与了 Aβ 清除机制的调节。在这项研究中，我们研究了年龄、性激素和昼夜节律对 Aβ 清道夫如载脂蛋白 J、胶凝蛋白和转甲状腺素蛋白在大鼠脉络丛中的表达的影响。我们的结果表明，研究的 Aβ 清道夫的 mRNA 表达以及细胞内和分泌蛋白水平均依赖于年龄、性别和昼夜节律。这些数据表明，由于衰老和昼夜节律紊乱，脉络丛中由 Aβ 清道夫介导的 Aβ 降解和清除途径可能受损。这些重要的发现增强了对血脑屏障中 Aβ 清除调节机制的理解。
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