Department of Pathology and Experimental Therapeutics, University of Barcelona, Hospitalet de Llobregat, Spain.
CIBERNED (Network Centre of Biomedical Research of Neurodegenerative Diseases), Institute of Health Carlos III, Hospitalet de Llobregat, Spain.
Brain Pathol. 2021 Nov;31(6):e12996. doi: 10.1111/bpa.12996. Epub 2021 Jul 4.
Tau hyperphosphorylation is the first step of neurofibrillary tangle (NFT) formation. In the present study, samples of the entorhinal cortex (EC) and frontal cortex area 8 (FC) of cases with NFT pathology classified as stages I-II, III-IV, and V-VI without comorbidities, and of middle-aged (MA) individuals with no NFT pathology, were analyzed by conventional label-free and SWATH-MS (sequential window acquisition of all theoretical fragment ion spectra mass spectrometry) to assess the (phospho)proteomes. The total number of identified dysregulated phosphoproteins was 214 in the EC, 65 of which were dysregulated at the first stages (I-II) of NFT pathology; 167 phosphoproteins were dysregulated in the FC, 81 of them at stages I-II of NFT pathology. A large percentage of dysregulated phosphoproteins were identified in the two regions and at different stages of NFT progression. The main group of dysregulated phosphoproteins was made up of components of the membranes, cytoskeleton, synapses, proteins linked to membrane transport and ion channels, and kinases. The present results show abnormal phosphorylation of proteins at the first stages of NFT pathology in the elderly (in individuals clinically considered representative of normal aging) and sporadic Alzheimer's disease (sAD). Dysregulated protein phosphorylation in the FC precedes the formation of NFTs and SPs. The most active period of dysregulated phosphorylation is at stages III-IV when a subpopulation of individuals might be clinically categorized as suffering from mild cognitive impairment which is a preceding determinant stage in the progression to dementia. Altered phosphorylation of selected proteins, carried out by activation of several kinases, may alter membrane and cytoskeletal functions, among them synaptic transmission and membrane/cytoskeleton signaling. Besides their implications in sAD, the present observations suggest a molecular substrate for "benign" cognitive deterioration in "normal" brain aging.
tau 过度磷酸化是神经原纤维缠结 (NFT) 形成的第一步。在本研究中，对无共病的 NFT 病理分类为 I-II 期、III-IV 期和 V-VI 期的额皮质 (EC) 和额前皮质 8 区 (FC) 以及无 NFT 病理的中年 (MA) 个体的 EC 和 FC 样本进行了分析，采用常规无标签和 SWATH-MS（顺序窗口采集所有理论片段离子谱质谱）来评估（磷酸化）蛋白质组。在 EC 中鉴定出 214 个失调磷酸化蛋白，其中 65 个在 NFT 病理的早期（I-II）阶段失调；在 FC 中鉴定出 167 个失调磷酸化蛋白，其中 81 个在 NFT 病理的 I-II 期失调。在两个区域和 NFT 进展的不同阶段，发现了大量失调的磷酸化蛋白。失调磷酸化蛋白的主要组成为膜、细胞骨架、突触、与膜转运和离子通道相关的蛋白质以及激酶的成分。本研究结果表明，在老年（在临床上被认为是正常衰老的个体）和散发性阿尔茨海默病（sAD）中，NFT 病理的早期阶段存在蛋白质异常磷酸化。FC 中蛋白磷酸化失调先于 NFT 和 SP 的形成。失调磷酸化最活跃的时期是在 III-IV 期，此时可能有一部分个体被临床归类为患有轻度认知障碍，这是向痴呆进展的前期决定阶段。一些激酶的激活改变了选定蛋白的磷酸化，可能会改变膜和细胞骨架的功能，其中包括突触传递和膜/细胞骨架信号转导。除了对 sAD 的影响外，本研究观察结果表明，在“正常”大脑衰老中，“良性”认知衰退有一个分子基础。
