Sanfilippo Cristina, Castrogiovanni Paola, Imbesi Rosa, Fagone Paolo, Scuderi Grazia, Vinciguerra Manlio, Di Rosa Michelino
Neurologic Unit, AOU "Policlinico-San Marco", Department of Medical, Surgical Sciences and Advanced Technologies, GF, Ingrassia, University of Catania, Via Santa Sofia N.78, 95100, Catania, Sicily, Italy.
Department of Biomedical and Biotechnological Sciences, Human Anatomy and Histology Section, School of Medicine, University of Catania, Catania, Italy.
Geroscience. 2025 Jun 14. doi: 10.1007/s11357-025-01740-4.
Synaptic pruning (SP) is a critical process in brain development and maintenance, essential for refining neural circuits by eliminating weak or redundant synapses. Dysregulation of SP has been implicated in neurodegenerative disorders such as Alzheimer's disease (AD). Studying the regulation of SP genes across the lifespan and their variation by sex and age is crucial to understanding the interplay between aging, sex, and AD pathogenesis. This study comprehensively analyzes the expression of SP-related genes, including complement system components (C1QA, C1QB, C1QC, C1S, C1R, C3), microglial regulators (ITGB2, ITGAM), and astrocytic factors (MERTK, MEGF10), as well as synaptic protective signals (CD47, SIRPA) in 2294 non-demented healthy controls (NDHC) and 1555 AD patients, stratified by sex, age, and brain area. Our findings reveal significant upregulation of most SP-related genes in AD brains, except for CD47 and SIRPA. Sex-specific patterns emerged, with males exhibiting stronger associations between complement genes and AD pathology, compared to females. Notably, in NDHC, females displayed higher baseline expression of SP-related genes (except CD47), but these sex differences diminished in AD, indicating disease-driven convergence. Age-related dynamics further highlighted distinct profiles, with males showing progressive upregulation of SP genes in NDHC, whereas females exhibited early senescence-like suppression followed by late-life compensatory changes. In AD, males demonstrated early complement dysregulation, while females displayed a pronounced inflammatory shift in advanced age. Region-specific analyses revealed heterogeneity, with the diencephalon showing the highest gene expression in NDHC males, while AD flattened regional differences in males but amplified variability in females. Correlation analyses linked complement and microglial genes to amyloid and tau pathology, with sex-specific associations. Principal component analysis (PCA) and Gene Ontology (GO) highlighted disrupted coordination between microglia, astrocytes, and neurons in AD. Protein expression analysis using the Human Protein Atlas revealed sex-specific differences in the localization of complement and microglial proteins in the prefrontal cortex. These findings underscore the complex interplay of sex, age, and regional factors in SP regulation, implicating complement overactivation, microglial dysfunction, and astrocytic phagocytosis in AD pathogenesis.
突触修剪（SP）是大脑发育和维持过程中的一个关键过程，对于通过消除薄弱或冗余突触来优化神经回路至关重要。SP的失调与神经退行性疾病如阿尔茨海默病（AD）有关。研究SP基因在整个生命周期中的调控及其随性别和年龄的变化，对于理解衰老、性别和AD发病机制之间的相互作用至关重要。本研究全面分析了SP相关基因的表达，包括补体系统成分（C1QA、C1QB、C1QC、C1S、C1R、C3）、小胶质细胞调节因子（ITGB2、ITGAM）和星形胶质细胞因子（MERTK、MEGF10），以及突触保护信号（CD47、SIRPA）在2294名非痴呆健康对照（NDHC）和1555名AD患者中的表达情况，并按性别、年龄和脑区进行分层。我们的研究结果显示，除了CD47和SIRPA外，AD大脑中大多数SP相关基因均显著上调。出现了性别特异性模式，与女性相比，男性的补体基因与AD病理之间的关联更强。值得注意的是，在NDHC中，女性显示出SP相关基因（CD47除外）的基线表达较高，但这些性别差异在AD中减弱，表明疾病驱动的趋同。与年龄相关的动态变化进一步突出了不同的特征，男性在NDHC中显示出SP基因的逐渐上调，而女性则表现出早期衰老样抑制，随后是晚年的代偿性变化。在AD中，男性表现出早期补体失调，而女性在高龄时表现出明显的炎症转变。区域特异性分析显示存在异质性，间脑在NDHC男性中显示出最高的基因表达，而AD使男性的区域差异变平，但增加了女性的变异性。相关性分析将补体和小胶质细胞基因与淀粉样蛋白和tau病理联系起来，存在性别特异性关联。主成分分析（PCA）和基因本体论（GO）突出了AD中小胶质细胞、星形胶质细胞和神经元之间协调的破坏。使用人类蛋白质图谱进行的蛋白质表达分析揭示了前额叶皮质中补体和小胶质细胞蛋白定位的性别特异性差异。这些发现强调了性别、年龄和区域因素在SP调控中的复杂相互作用，提示补体过度激活、小胶质细胞功能障碍和星形胶质细胞吞噬作用在AD发病机制中的作用。
