Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000 Bordeaux, France; Faculté de pharmacie, Université Laval, Québec, Québec, Canada; Centre de recherche du CHU de Québec-Université Laval (CHUL), Axe Neurosciences, 2705 Boulevard Laurier, Québec, Québec, Canada; Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Québec, Québec, Canada; LIA OptiNutriBrain - Laboratoire International Associé (NutriNeuro France-INAF Canada), Canada.
Faculté de pharmacie, Université Laval, Québec, Québec, Canada; Centre de recherche du CHU de Québec-Université Laval (CHUL), Axe Neurosciences, 2705 Boulevard Laurier, Québec, Québec, Canada.
Neurobiol Dis. 2021 Dec;161:105542. doi: 10.1016/j.nbd.2021.105542. Epub 2021 Nov 1.
Vitamin A (VitA), via its active metabolite retinoic acid (RA), is critical for the maintenance of memory function with advancing age. Although its role in Alzheimer's disease (AD) is not well understood, data suggest that impaired brain VitA signaling is associated with the accumulation of β-amyloid peptides (Aβ), and could thus contribute to the onset of AD.
We evaluated the protective action of a six-month-long dietary VitA-supplementation (20 IU/g), starting at 8 months of age, on the memory and the neuropathology of the 3xTg-AD mouse model of AD (n = 11-14/group; including 4-6 females and 7-8 males). We also measured protein levels of Retinoic Acid Receptor β (RARβ) and Retinoid X Receptor γ (RXRγ) in homogenates from the inferior parietal cortex of 60 participants of the Religious Orders study (ROS) divided in three groups: no cognitive impairment (NCI) (n = 20), mild cognitive impairment (MCI) (n = 20) and AD (n = 20).
The VitA-enriched diet preserved spatial memory of 3xTg-AD mice in the Y maze. VitA-supplementation affected hippocampal RXR expression in an opposite way according to sex by tending to increase in males and decrease in females their mRNA expression. VitA-enriched diet also reduced the amount of hippocampal Aβ and Aβ, as well as the phosphorylation of tau protein at sites Ser396/Ser404 (PHF-1) in males. VitA-supplementation had no effect on tau phosphorylation in females but worsened their hippocampal Aβ load. However, the expression of Rxr-β in the hippocampus was negatively correlated with the amount of both soluble and insoluble Aβ in both males and females. Western immunoblotting in the human cortical samples of the ROS study did not reveal differences in RARβ levels. However, it evidenced a switch from a 60-kDa-RXRγ to a 55-kDa-RXRγ in AD, correlating with ante mortem cognitive decline and the accumulation of neuritic plaques in the brain cortex.
Our data suggest that (i) an altered expression of RXRs receptors is a contributor to β-amyloid pathology in both humans and 3xTg-AD mice, (ii) a chronic exposure of 3xTg-AD mice to a VitA-enriched diet may be protective in males, but not in females.
维生素 A（VitA）通过其活性代谢产物视黄酸（RA），对于维持随着年龄增长的记忆功能至关重要。尽管其在阿尔茨海默病（AD）中的作用尚未完全了解，但数据表明，受损的大脑 VitA 信号与 β-淀粉样肽（Aβ）的积累有关，因此可能导致 AD 的发生。
我们评估了从 8 个月大开始，为期 6 个月的富含 VitA 的饮食补充（20 IU/g）对 3xTg-AD 小鼠 AD 模型的记忆和神经病理学的保护作用（n=11-14/组；包括 4-6 名女性和 7-8 名男性）。我们还测量了 60 名宗教秩序研究（ROS）参与者的下顶叶皮质匀浆中视黄酸受体 β（RARβ）和视黄醛 X 受体 γ（RXRγ）的蛋白水平，这些参与者分为三组：无认知障碍（NCI）（n=20）、轻度认知障碍（MCI）（n=20）和 AD（n=20）。
富含 VitA 的饮食可改善 3xTg-AD 小鼠在 Y 迷宫中的空间记忆。VitA 补充根据性别以相反的方式影响海马 RXR 表达，倾向于增加雄性的 mRNA 表达，减少雌性的表达。富含 VitA 的饮食还减少了海马体 Aβ和 Aβ的含量，以及 Ser396/Ser404 位点（PHF-1）的 tau 蛋白磷酸化在雄性中。VitA 补充对雌性 tau 磷酸化没有影响，但加重了其海马体 Aβ的负荷。然而，在雄性和雌性中，海马 Rxr-β的表达与可溶性和不溶性 Aβ的含量均呈负相关。ROS 研究中人类皮质样本的 Western 免疫印迹未显示 RARβ 水平的差异。然而，它证明了 AD 中从 60kDa-RXRγ到 55kDa-RXRγ的转变，与生前认知衰退和大脑皮质神经原纤维缠结的积累相关。
我们的数据表明，（i）RXR 受体的表达改变是人类和 3xTg-AD 小鼠 β-淀粉样蛋白病理的一个贡献因素，（ii）3xTg-AD 小鼠长期暴露于富含 VitA 的饮食可能对雄性具有保护作用，但对雌性没有作用。
