Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL.
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL.
Ann Neurol. 2018 Jul;84(1):78-88. doi: 10.1002/ana.25266. Epub 2018 Jul 3.
Previous gene expression analysis identified a network of coexpressed genes that is associated with β-amyloid neuropathology and cognitive decline in older adults. The current work targeted influential genes in this network with quantitative proteomics to identify potential novel therapeutic targets.
Data came from 834 community-based older persons who were followed annually, died, and underwent brain autopsy. Uniform structured postmortem evaluations assessed the burden of β-amyloid and other common age-related neuropathologies. Selected reaction monitoring quantified cortical protein abundance of 12 genes prioritized from a molecular network of aging human brain that is implicated in Alzheimer's dementia. Regression and linear mixed models examined the protein associations with β-amyloid load and other neuropathological indices as well as cognitive decline over multiple years preceding death.
Average age at death was 88.6 years. Overall, 349 participants (41.9%) had Alzheimer's dementia at death. A higher level of PLXNB1 abundance was associated with more β-amyloid load (p = 1.0 × 10 ) and higher PHFtau tangle density (p = 2.3 × 10 ), and the association of PLXNB1 with cognitive decline is mediated by these known Alzheimer's disease pathologies. On the other hand, higher IGFBP5, HSPB2, and AK4 and lower ITPK1 levels were associated with faster cognitive decline, and, unlike PLXNB1, these associations were not fully explained by common neuropathological indices, suggesting novel mechanisms leading to cognitive decline.
Using targeted proteomics, this work identified cortical proteins involved in Alzheimer's dementia and begins to dissect two different molecular pathways: one affecting β-amyloid deposition and another affecting resilience without a known pathological footprint. Ann Neurol 2018;83:78-88.
先前的基因表达分析确定了一个与老年人大脑中β-淀粉样蛋白病理和认知能力下降相关的共表达基因网络。目前的工作旨在通过定量蛋白质组学靶向该网络中的有影响力的基因，以确定潜在的新治疗靶点。
数据来自 834 名基于社区的老年人，他们每年接受随访，死亡并接受脑尸检。统一的结构化死后评估评估了β-淀粉样蛋白和其他常见与年龄相关的神经病理学的负担。选择反应监测定量了从涉及阿尔茨海默病痴呆的人类大脑衰老分子网络中优先选择的 12 个基因的皮质蛋白丰度。回归和线性混合模型检查了蛋白质与β-淀粉样蛋白负荷和其他神经病理学指标以及死亡前多年认知能力下降的相关性。
平均死亡年龄为 88.6 岁。总体而言，349 名参与者（41.9％）在死亡时患有阿尔茨海默病痴呆症。较高的 PLXNB1 丰度与较高的β-淀粉样蛋白负荷（p=1.0×10）和较高的 PHFtau 缠结密度（p=2.3×10）相关，并且 PLXNB1 与认知能力下降的相关性由这些已知的阿尔茨海默病病理学介导。另一方面，较高的 IGFBP5、HSPB2 和 AK4 水平和较低的 ITPK1 水平与认知能力下降较快相关，与 PLXNB1 不同，这些相关性不能完全由常见的神经病理学指标解释，表明导致认知能力下降的新机制。
使用靶向蛋白质组学，本工作鉴定了涉及阿尔茨海默病痴呆症的皮质蛋白，并开始剖析两种不同的分子途径：一种影响β-淀粉样蛋白沉积，另一种影响没有已知病理足迹的弹性。安神经学 2018;83:78-88。
