Lysosomal Health in Ageing, Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia; Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia.
Lysosomal Health in Ageing, Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia.
J Nutr. 2023 May;153(5):1407-1419. doi: 10.1016/j.tjnut.2023.02.035. Epub 2023 Mar 3.
Alzheimer disease (AD) is a neurodegenerative condition defined by the build-up of amyloid plaques in the brain and intraneuronal tangles of the protein tau. Autophagy is a cellular cleaning process involved in the degradation of proteins, including proteins directly responsible for amyloid plaques, but its activity is compromised in AD. The mechanistic target of rapamycin complex (mTORC) 1 inhibits autophagy when activated by amino acids.
We hypothesized that reducing amino acid intake by decreasing dietary protein could promote autophagy, which in turn could prevent amyloid plaque deposition in AD mice.
Homozygote (2-mo-old) and heterozygote (4-mo-old) amyloid precursor protein NL-G-F mice, a model of brain amyloid deposition, were used in this study to test this hypothesis. Male and female mice were fed with isocaloric low-protein, control, or high-protein diets for 4 mo and killed for analysis. Locomotor performance was measured using the inverted screen test, and body composition was measured using EchoMRI. Samples were analyzed using western blotting, enzyme-linked immunosorbent assay, mass spectrometry, and immunohistochemical staining.
mTORC1 activity in the cerebral cortex was inversely covaried with protein consumption in both homozygote and heterozygote mice. Low-protein diet improved metabolic parameters and restored locomotor performance only in male homozygous mice. Dietary protein adjustment did not affect amyloid deposition in homozygous mice. However, in the heterozygous amyloid precursor protein NL-G-F mice, amyloid plaque was lower in male mice consuming the low protein compared with that in mice fed with the control diet.
This study showed that reducing protein intake reduces mTORC1 activity and may prevent amyloid accumulation, at least in male mice. Moreover, dietary protein is a tool that can be used to change mTORC1 activity and amyloid deposition in the mouse brain, and the murine brain's response to dietary protein is sex specific.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是大脑中淀粉样斑块的积累和蛋白质tau 的神经元内缠结。自噬是一种参与蛋白质降解的细胞清洁过程，包括直接导致淀粉样斑块的蛋白质，但在 AD 中其活性受到损害。雷帕霉素复合物（mTORC）1 的机械靶标在被氨基酸激活时抑制自噬。
我们假设通过减少饮食中的蛋白质来减少氨基酸的摄入可以促进自噬，从而防止 AD 小鼠中淀粉样斑块的沉积。
本研究使用同型（2 个月大）和杂合子（4 个月大）淀粉样前体蛋白 NL-G-F 小鼠，这是一种脑淀粉样沉积模型，来检验这一假设。雄性和雌性小鼠分别用等热量的低蛋白、对照或高蛋白饮食喂养 4 个月，并进行分析。使用倒置屏幕测试测量运动表现，使用 EchoMRI 测量身体成分。使用 Western 印迹、酶联免疫吸附测定、质谱和免疫组织化学染色分析样品。
同型和杂合子小鼠大脑皮质中的 mTORC1 活性与蛋白质消耗呈负相关。低蛋白饮食仅改善了雄性同型小鼠的代谢参数和运动表现。饮食蛋白调整对同型小鼠的淀粉样沉积没有影响。然而，在杂合子淀粉样前体蛋白 NL-G-F 小鼠中，与对照组相比，雄性小鼠摄入低蛋白饮食时淀粉样斑块较少。
本研究表明，减少蛋白质摄入可降低 mTORC1 活性，至少可预防雄性小鼠的淀粉样蛋白积聚。此外，饮食蛋白是一种可以用来改变小鼠大脑中 mTORC1 活性和淀粉样蛋白沉积的工具，而小鼠大脑对饮食蛋白的反应具有性别特异性。
