Wyatt-Johnson Season K, Ackley Samantha, Warren Jalyn, Priya Raj, Wan Jun, Liu Sheng, Brutkiewicz Randy R
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Alzheimers Dement. 2025 Feb;21(2):e14480. doi: 10.1002/alz.14480. Epub 2025 Jan 8.
Plaques are a hallmark feature of Alzheimer's disease (AD). We found that the loss of mucosal-associated invariant T (MAIT) cells and their antigen-presenting molecule MR1 caused a delay in plaque pathology development in AD mouse models. However, it remains unknown how this axis is impacting dystrophic neurites.
Brain tissue from 5XFAD mice and those that are MR1 deficient (MR1 KO), were analyzed for dystrophic neurites, amyloid plaques, and synapses via immunofluorescence, RNA sequencing, enzyme-linked immunosorbent assay, and western blot.
In 8-month-old 5XFAD/MR1 KO mice, there was reduced expression of lysosomal-associated membrane protein 1, ubiquitin, and n-terminal amyloid precursor protein in the hippocampus compared to 5XFAD mice (P < 0.05). 5XFAD/MR1 KO mice also had less insoluble amyloid beta 40 (P < 0.001) and higher levels of postsynaptic density protein 95 (P < 0.01) in the hippocampus.
Our data contribute additional mechanistic insight into the detrimental role of the MR1/MAIT cell axis in AD pathology development.
5XFAD mice lacking the innate immune MR1/MAIT (mucosal-associated invariant T) cell axis (5XFAD/MR1 KO) have reduced numbers of dystrophic neurite markers in the hippocampus at 8 months of age. Hippocampal tissue transcriptional analyses showed reduced expression of genes encoding classical dystrophic neurite markers in 5XFAD/MR1 KO mice. 5XFAD/MR1 KO mice had less insoluble amyloid beta 40 and increased levels of the post-synaptic marker, postsynaptic density protein 95, in the hippocampus than did MR1+ 5XFAD mice.
斑块是阿尔茨海默病（AD）的标志性特征。我们发现黏膜相关恒定T（MAIT）细胞及其抗原呈递分子MR1的缺失导致AD小鼠模型中斑块病理学发展延迟。然而，该轴如何影响营养不良性神经突仍不清楚。
通过免疫荧光、RNA测序、酶联免疫吸附测定和蛋白质免疫印迹法，对5XFAD小鼠和MR1缺陷（MR1敲除）小鼠的脑组织进行营养不良性神经突、淀粉样斑块和突触分析。
与5XFAD小鼠相比，8月龄的5XFAD/MR1敲除小鼠海马中溶酶体相关膜蛋白1、泛素和淀粉样前体蛋白N端的表达降低（P<0.05）。5XFAD/MR1敲除小鼠海马中不溶性淀粉样β40也较少（P<0.001），突触后致密蛋白95水平较高（P<0.01）。
我们的数据为MR1/MAIT细胞轴在AD病理发展中的有害作用提供了更多的机制性见解。
缺乏先天免疫MR1/MAIT（黏膜相关恒定T）细胞轴的5XFAD小鼠（5XFAD/MR1敲除）在8月龄时海马中营养不良性神经突标志物数量减少。海马组织转录分析显示，5XFAD/MR1敲除小鼠中编码经典营养不良性神经突标志物的基因表达降低。与MR1+5XFAD小鼠相比，5XFAD/MR1敲除小鼠海马中不溶性淀粉样β40较少，突触后标志物突触后致密蛋白95水平升高。
