From the Rush Alzheimer's Disease Center (A.S.B., L.Y., A.R.Z., S.O., S.N., D.A.B.); Department of Neurological Sciences (A.S.B., L.Y., S.O., D.A.B.), Rush University Medical Center, Chicago, IL; Center for Translational and Computational Neuroimmunology (H.-U.K.), Department of Neurology, Columbia University Medical Center, New York; Department of Pathology (Neuropathology) (S.N.), Rush University Medical Center, Chicago, IL; Katz Institute for Nanoscale Science and Technology Ben Gurion University (N.T.), Beer Sheva; The de Botton Institute for Protein Profiling (H.L., D.M., Y.L.), Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel; Department of Neurology (N.S.), Emory University School of Medicine; Department of Biochemistry (N.S.), Emory University, Atlanta, GA; and Department of Neurology (M.S.B.), Rutgers Robert Wood Johnson Medical School and Rutgers Brain Health Institute, NJ.
Neurology. 2024 Apr 9;102(7):e209223. doi: 10.1212/WNL.0000000000209223. Epub 2024 Mar 19.
Molecular omics studies have identified proteins related to cognitive resilience but unrelated to Alzheimer disease and Alzheimer disease-related dementia (AD/ADRD) pathologies. Posttranslational modifications of proteins with glycans can modify protein function. In this study, we identified glycopeptiforms associated with cognitive resilience.
We studied brains from adults with annual cognitive testing with postmortem indices of 10 AD/ADRD pathologies and proteome-wide data from dorsal lateral prefrontal cortex (DLPFC). We quantified 11, 012 glycopeptiforms from DLPFC using liquid chromatography with tandem mass spectrometry. We used linear mixed-effects models to identify glycopeptiforms associated with cognitive decline correcting for multiple comparisons ( < 5 × 10). Then, we regressed out the effect of AD/ADRD pathologies to identify glycopeptiforms that may provide cognitive resilience.
We studied 366 brains, average age at death 89 years, and 70% female with no cognitive impairment = 152, mild cognitive impairment = 93, and AD = 121 cognitive status at death. In models adjusting for age, sex and education, 11 glycopeptiforms were associated with cognitive decline. In further modeling, 8 of these glycopeptiforms remained associated with cognitive decline after adjusting for AD/ADRD pathologies: NPTX2a (Est., 0.030, SE, 0.005, = 1 × 10); NPTX2b (Est.,0.019, SE, 0.005, = 2 × 10) NECTIN1(Est., 0.029, SE, 0.009, = 9 × 10), NPTX2c (Est., 0.015, SE, 0.004, = 9 × 10), HSPB1 (Est., -0.021, SE, 0.006, = 2 × 10), PLTP (Est., -0.027, SE, 0.009, = 4.2 × 10), NAGK (Est., -0.027, SE, 0.008, = 1.4 × 10), and VAT1 (Est., -0.020, SE, 0.006, = 1.1 × 10). Higher levels of 4 resilience glycopeptiforms derived through glycosylation were associated with slower decline and higher levels of 4 derived through glycation were related to faster decline. Together, these 8 glycopeptiforms accounted for an additional 6% of cognitive decline over the 33% accounted for the 10 brain pathologies and demographics. All 8 resilience glycopeptiforms remained associated with cognitive decline after adjustments for the expression level of their corresponding protein. Exploratory gene ontology suggested that molecular mechanisms of glycopeptiforms associated with cognitive decline may involve metabolic pathways including pyruvate and NADH pathways and highlighted the importance of molecular mechanisms involved in glucose metabolism.
Glycopeptiforms in aging brains may provide cognitive resilience. Targeting these glycopeptiforms may lead to therapies that maintain cognition through resilience.
分子组学研究已经确定了与认知弹性相关但与阿尔茨海默病和阿尔茨海默病相关痴呆症（AD/ADRD）病理无关的蛋白质。糖蛋白的翻译后修饰可以改变蛋白质的功能。在这项研究中，我们鉴定了与认知弹性相关的糖肽。
我们研究了具有年度认知测试和死后 AD/ADRD 病理学 10 项指标以及背外侧前额叶皮质（DLPFC）的蛋白质组学数据的成年人的大脑。我们使用液相色谱-串联质谱法从 DLPFC 中定量了 11012 种糖肽。我们使用线性混合效应模型来识别与认知下降相关的糖肽，同时纠正了多重比较（<5×10）。然后，我们回归了 AD/ADRD 病理学的影响，以识别可能提供认知弹性的糖肽。
我们研究了 366 个大脑，平均死亡年龄为 89 岁，70%为女性，无认知障碍=152 例，轻度认知障碍=93 例，AD=121 例。在调整年龄、性别和教育的模型中，有 11 种糖肽与认知下降相关。在进一步的建模中，在调整 AD/ADRD 病理学后，其中 8 种糖肽仍然与认知下降相关：NPTX2a（估计值，0.030，SE，0.005，=1×10）；NPTX2b（估计值，0.019，SE，0.005，=2×10）NECTIN1（估计值，0.029，SE，0.009，=9×10），NPTX2c（估计值，0.015，SE，0.004，=9×10），HSPB1（估计值，-0.021，SE，0.006，=2×10），PLTP（估计值，-0.027，SE，0.009，=4.2×10），NAGK（估计值，-0.027，SE，0.008，=1.4×10），和 VAT1（估计值，-0.020，SE，0.006，=1.1×10）。通过糖基化衍生的 4 种具有恢复力的糖肽水平较高与下降较慢相关，而通过糖化衍生的 4 种糖肽水平较高与下降较快相关。总的来说，这 8 种糖肽在 33%的脑病理学和人口统计学解释的认知下降中额外解释了 6%。在调整其相应蛋白质表达水平后，所有 8 种具有恢复力的糖肽仍然与认知下降相关。探索性的基因本体论表明，与认知下降相关的糖肽的分子机制可能涉及代谢途径，包括丙酮酸和 NADH 途径，并强调了与葡萄糖代谢相关的分子机制的重要性。
衰老大脑中的糖肽可能提供认知弹性。针对这些糖肽可能会导致通过弹性维持认知的治疗方法。
