Department of Pathology and Laboratory Medicine, University of Texas Health Science Center, San Antonio, TX, USA.
Department of Pathology, Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center, 7703 Floyd Curl Dr., MC 8070, San Antonio, TX, 78229-3900, USA.
Acta Neuropathol Commun. 2022 Feb 14;10(1):23. doi: 10.1186/s40478-022-01324-9.
Clinical symptoms correlate with underlying neurodegenerative changes in the vast majority of people. However, an intriguing group of individuals demonstrate neuropathologic changes consistent with Alzheimer disease (AD) yet remain cognitively normal (termed "resilient"). Previous studies have reported less overall neuronal loss, less gliosis, and fewer comorbidities in these individuals. Herein, NanoString GeoMx™ Digital Spatial Profiler (DSP) technology was utilized to investigate protein expression differences comparing individuals with dementia and AD neuropathologic change to resilient individuals. DSP allows for spatial analysis of protein expression in multiple regions of interest (ROIs) on formalin-fixed paraffin-embedded sections. ROIs in this analysis were hippocampal neurofibrillary tangle (NFT)-bearing neurons, non-NFT-bearing neurons, and their immediate neuronal microenvironments. Analyses of 86 proteins associated with CNS cell-typing or known neurodegenerative changes in 168 ROIs from 14 individuals identified 11 proteins displaying differential expression in NFT-bearing neurons of the resilient when compared to the demented (including APP, IDH1, CD68, GFAP, SYP and Histone H3). In addition, IDH1, CD68, and SYP were differentially expressed in the environment of NFT-bearing neurons when comparing resilient to demented. IDH1 (which is upregulated under energetic and oxidative stress) and PINK1 (which is upregulated in response to mitochondrial dysfunction and oxidative stress) both displayed lower expression in the environment of NFT-bearing neurons in the resilient. Therefore, the resilient display less evidence of energetic and oxidative stress. Synaptophysin (SYP) was increased in the resilient, which likely indicates better maintenance of synapses and synaptic connections. Furthermore, neurofilament light chain (NEFL) and ubiquitin c-terminal hydrolase (Park5) were higher in the resilient in the environment of NFTs. These differences all suggest healthier intact axons, dendrites and synapses in the resilient. In conclusion, resilient individuals display protein expression patterns suggestive of an environment containing less energetic and oxidative stress, which in turn results in maintenance of neurons and their synaptic connections.
临床症状与绝大多数人潜在的神经退行性变化相关。然而，有一群有趣的人表现出与阿尔茨海默病（AD）一致的神经病理学变化，但认知仍然正常（称为“有弹性”）。以前的研究报告称，这些人总的神经元损失较少，神经胶质增生较少，合并症较少。在此，利用 NanoString GeoMx™数字空间分析器（DSP）技术比较痴呆和 AD 神经病理学改变与有弹性的个体，研究蛋白质表达差异。DSP 允许对福尔马林固定石蜡包埋切片的多个感兴趣区域（ROI）的蛋白质表达进行空间分析。该分析中的 ROI 是海马神经原纤维缠结（NFT）携带神经元、非 NFT 携带神经元及其直接神经元微环境。对 14 名个体的 168 个 ROI 中与 CNS 细胞分型或已知神经退行性变化相关的 86 种蛋白质的分析，确定了 11 种在与痴呆相比时在有弹性的 NFT 携带神经元中表达差异的蛋白质（包括 APP、IDH1、CD68、GFAP、SYP 和组蛋白 H3）。此外，在比较有弹性和痴呆时，IDH1、CD68 和 SYP 在 NFT 携带神经元的环境中表达不同。IDH1（在能量和氧化应激下上调）和 PINK1（对线粒体功能障碍和氧化应激上调）在有弹性的 NFT 携带神经元环境中的表达均较低。因此，有弹性的显示出较少的能量和氧化应激证据。突触小体相关蛋白（SYP）在有弹性的中增加，这可能表明突触和突触连接得到更好的维持。此外，神经丝轻链（NEFL）和泛素 C 端水解酶（Park5）在有弹性的 NFT 环境中更高。这些差异都表明有弹性的具有更健康的完整轴突、树突和突触。总之，有弹性的个体表现出的蛋白质表达模式表明，其环境中能量和氧化应激较少，从而维持神经元及其突触连接。
