全蛋白质组分析鉴定出与不同认知能力的韧性相关的皮质蛋白。
Proteome-wide Analyses Identified Cortical Proteins Associated With Resilience for Varied Cognitive Abilities.
机构信息
From the Rush Alzheimer's Disease Center (A.R.Z., L.Y., J.A.S., D.A.B., A.S.B.), and Departments of Psychiatry and Behavioral Sciences (A.R.Z.), Neurological Sciences (L.Y., J.A.S., D.A.B., A.S.B.), and Pathology (J.A.S.), Rush University Medical Center, Chicago, IL; Department of Neurology (H.-U.K.), Columbia University Medical Center, New York, NY; Departments of Neurology (A.I.L., N.T.S., T.S.W.) Psychiatry (A.P.W.), and Human Genetics (T.S.W.), and the Goizueta Alzheimer's Disease Center (T.S.W.), Emory University School of Medicine, Atlanta, GA; Department of Biochemistry (N.T.S.), Emory University, Atlanta, GA; and Division of Mental Health (A.P.W.), Atlanta VA Medical Center, Decatur, GA.
出版信息
Neurology. 2024 Jan 9;102(1):e207816. doi: 10.1212/WNL.0000000000207816. Epub 2023 Dec 15.
BACKGROUND AND OBJECTIVES
Prior work suggests that cognitive resilience may contribute to the heterogeneity of cognitive decline. This study examined whether distinct cortical proteins provide resilience for different cognitive abilities.
METHODS
Participants were from the Religious Orders Study or the Rush Memory and Aging Project who had undergone annual assessments of 5 cognitive abilities and postmortem assessment of 9 Alzheimer disease and related dementia (ADRD) pathologies. Proteome-wide examination of the dorsolateral prefrontal cortex using tandem mass tag and liquid chromatography-mass spectrometry yielded 8,425 high-abundance proteins. We applied linear mixed-effect models to quantify residual cognitive change (cognitive resilience) of 5 cognitive abilities by regressing out cognitive decline related to age, sex, education, and indices of ADRD pathologies. Then we added terms for each of the individual proteins to identify cognitive resilience proteins associated with the different cognitive abilities.
RESULTS
We included 604 decedents (69% female; mean age at death = 89 years) with proteomic data. A total of 47 cortical proteins that provide cognitive resilience were identified: 22 were associated with specific cognitive abilities, and 25 were common to at least 2 cognitive abilities. NRN1 was the only protein that was associated with more than 2 cognitive abilities (semantic memory: estimate = 0.020, SE = 0.004, = 2.2 × 10; episodic memory: estimate = 0.029, SE = 0.004, = 5.8 × 10; and working memory: estimate = 0.021, SE = 0.004, = 1.2 × 10). Exploratory gene ontology analysis suggested that among top molecular pathways, mitochondrial translation was a molecular mechanism providing resilience in episodic memory, while nuclear-transcribed messenger RNA catabolic processes provided resilience in working memory.
DISCUSSION
This study identified cortical proteins associated with various cognitive abilities. Differential associations across abilities may reflect distinct underlying biological pathways. These data provide potential high-value targets for further mechanistic and drug discovery studies to develop targeted treatments to prevent loss of cognition.
背景与目的
先前的研究表明认知弹性可能有助于认知衰退的异质性。本研究检验了不同皮质蛋白是否为不同的认知能力提供弹性。
方法
参与者来自宗教秩序研究或拉什记忆与衰老项目，他们接受了 5 项认知能力的年度评估和死后 9 项阿尔茨海默病及相关痴呆症（ADRD）病理的评估。使用串联质量标签和液相色谱-质谱法对背外侧前额叶皮层进行了全蛋白质组学检测，得到了 8425 种高丰度蛋白质。我们应用线性混合效应模型，通过回归与年龄、性别、教育和 ADRD 病理指标相关的认知衰退，量化 5 种认知能力的残余认知变化（认知弹性）。然后，我们为每个单独的蛋白质添加了一个术语，以确定与不同认知能力相关的认知弹性蛋白。
结果
我们纳入了 604 名死者（69%为女性；死亡时的平均年龄为 89 岁），他们具有蛋白质组学数据。共确定了 47 种提供认知弹性的皮质蛋白：22 种与特定认知能力相关，25 种与至少 2 种认知能力相关。NRN1 是唯一与 2 种以上认知能力相关的蛋白质（语义记忆：估计值=0.020，SE=0.004，=2.2×10；情节记忆：估计值=0.029，SE=0.004，=5.8×10；工作记忆：估计值=0.021，SE=0.004，=1.2×10）。探索性基因本体分析表明，在顶级分子途径中，线粒体翻译是提供情节记忆弹性的分子机制，而核转录信使 RNA 分解代谢过程则为工作记忆提供弹性。
讨论
本研究鉴定了与各种认知能力相关的皮质蛋白。能力之间的差异关联可能反映了不同的潜在生物学途径。这些数据为进一步的机制和药物发现研究提供了潜在的高价值靶点，以开发靶向治疗方法来预防认知丧失。
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