Department of Pharmacology, University of the Basque Country (EHU/UPV) and Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Barrio Sarriena S/N, 48940, Leioa, Spain.
Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.
Acta Neuropathol. 2021 May;141(5):755-770. doi: 10.1007/s00401-021-02282-7. Epub 2021 Mar 1.
Age-related neuropathologies progressively impair cognitive abilities by damaging synaptic function. We aimed to identify key components within the presynaptic SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) machinery associated with cognitive performance and estimate their potential contribution to brain reserve in old age. We used targeted SRM proteomics to quantify amounts of 60 peptides, encoded in 30 different genes, in postmortem specimens of the prefrontal cortex from 1209 participants of two aging studies, with available antemortem cognitive evaluations and postmortem neuropathologic assessments. We found that select (but not all) proteoforms are strongly associated with cognitive function and the burden of Alzheimer's disease (AD) pathology. Specifically, greater abundance of STX1A (but not other syntaxins), SYT12, full-length SNAP25, and the GABAergic STXBP1 variant were robustly associated with better cognitive performance. By contrast, greater abundance of other presynaptic proteins (e.g., STXBP5 or tomosyn, STX7, or SYN2) showed a negative influence on cognition. Regression models adjusting for demographic and pathologic variables showed that altered levels of these protein species explained 7.7% additional between-subject variance in cognition (more than any individual age-related neuropathology in the model), suggesting that these molecules constitute key elements of brain reserve. Network analyses indicated that those peptides associated with brain reserve, and closest to the SNARE fusogenic activity, showed greater centrality measures and were better connected in the network. Validation assays confirmed the selective loss of the STX1A (but not STX1B) isoform in cognitively impaired cases. In rodent and human brains, STX1A was selectively located at glutamatergic terminals. However, in AD brains, STX1A was redistributed adjacent to neuritic pathology, and markedly expressed in astrocytes. Our study provides strong evidence, indicating that select presynaptic proteins are key in maintaining brain reserve. Compromised ability to sustain expression levels of these proteins may trigger synaptic dysfunction and concomitant cognitive impairment.
年龄相关性神经病理学通过损害突触功能逐渐损害认知能力。我们旨在确定与认知表现相关的突触前 SNARE（可溶性 N-乙基马来酰亚胺敏感因子附着蛋白受体）机制中的关键成分，并估计它们对老年大脑储备的潜在贡献。我们使用靶向 SRM 蛋白质组学来定量 1209 名两项衰老研究的死后前额叶皮层标本中的 30 个不同基因编码的 60 个肽的量，这些标本具有可用的生前认知评估和死后神经病理学评估。我们发现，选择（但不是全部）蛋白质与认知功能和阿尔茨海默病（AD）病理负担强烈相关。具体而言，STX1A（而不是其他突触素）、SYT12、全长 SNAP25 和 GABA 能 STXBP1 变体的丰度与更好的认知表现密切相关。相比之下，其他突触前蛋白（例如 STXBP5 或 tomosyn、STX7 或 SYN2）的丰度增加对认知产生负面影响。调整人口统计学和病理学变量的回归模型表明，这些蛋白质种类的改变水平解释了认知方面 7.7%的受试者间差异（比模型中的任何一种与年龄相关的神经病理学都多），表明这些分子构成了大脑储备的关键要素。网络分析表明，与大脑储备相关的肽，并且最接近 SNARE 融合活性，显示出更高的中心度度量值，并且在网络中连接更好。验证实验证实了认知障碍病例中选择性缺失 STX1A（而不是 STX1B）同工型。在啮齿动物和人类大脑中，STX1A 选择性地位于谷氨酸能末梢。然而，在 AD 大脑中，STX1A 被重新分布在神经原性病变附近，并在星形胶质细胞中明显表达。我们的研究提供了强有力的证据，表明某些突触前蛋白是维持大脑储备的关键。这些蛋白质表达水平维持能力受损可能会引发突触功能障碍和随之而来的认知障碍。
