Contreras Ana, Jiménez-Herrera Raquel, Djebari Souhail, Navarro-López Juan D, Jiménez-Díaz Lydia
Neurophysiology & Behavior Lab, Biomedicine Institute (IB-UCLM), School of Medicine of Ciudad Real, University of Castilla-La Mancha, Ciudad Real, 13071, Spain.
Biol Sex Differ. 2025 May 25;16(1):36. doi: 10.1186/s13293-025-00697-5.
Hippocampal dysfunction induced by soluble amyloid-β oligomers (oAβ) is an early neuropathological hallmark of Alzheimer's disease (AD). oAβ shifts hippocampal synaptic-plasticity induction threshold facilitating long-term depression (LTD) instead of long-term potentiation (LTP, the functional basis of memory), thereby leading to memory deficits in early AD-like amyloidosis mouse models. In this regard, the spatial distribution of the underlying synaptic-plasticity/memory proteome changes in the hippocampus, and potential sex differences, remain unknown. Here we postulated that some protein changes related to synaptic-plasticity and memory may be unique to sex and/or specific to the dorsal or ventral hippocampus -as both regions have distinct functionality and connectivity-, potentially providing sex- and spatial-specific proteomic phenotypes for early AD-amyloidosis interventions.
An innovative spatial-resolution proteomics study was performed to map whole hippocampal proteome distribution using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry. For this purpose, sixteen adult male and female mouse brains intracerebroventricularly injected with oAβ/vehicle were analyzed. MALDI-imaging RapifleXTM-MALDI-TissuetyperTM TOF/TOF mass spectrometer was used, followed by traditional tandem mass spectrometry (MS/MS) for precise protein identification on tissue.
34 proteins showed significant differences in expression levels due to treatment, sex, or hippocampal location among 234 peptides initially detected; and displayed significant protein-protein interaction (PPI), indicating main functional relationship to LTP/LTD pathways and memory. Thus, 14 proteins related to synaptic-plasticity and/or AD were further studied, showing that most modulated glycogen synthase kinase-3β (GSK-3β), a protein widely involved in synaptic-plasticity induction threshold regulation towards LTD. Accordingly, hippocampal GSK-3β was found to be overactivated in AD-like amyloidosis mice.
We show for the first-time specific sex-dependent synaptic-plasticity proteome changes in dorsal/ventral hippocampi that modulate GSK-3β activity. These findings provide new insight into the early amyloidosis pathogenesis in AD and offer valuable, unique proteomic phenotypes as potential biomarkers and targets for early diagnosis and therapy in both sexes.
可溶性淀粉样蛋白-β寡聚体（oAβ）诱导的海马功能障碍是阿尔茨海默病（AD）的早期神经病理学标志。oAβ改变海马突触可塑性诱导阈值，促进长时程抑制（LTD）而非长时程增强（LTP，记忆的功能基础），从而导致早期AD样淀粉样变性小鼠模型出现记忆缺陷。在这方面，海马中潜在的突触可塑性/记忆蛋白质组变化的空间分布以及潜在的性别差异仍然未知。在这里，我们推测一些与突触可塑性和记忆相关的蛋白质变化可能具有性别特异性和/或特定于背侧或腹侧海马——因为这两个区域具有不同的功能和连接性——这可能为早期AD淀粉样变性干预提供性别和空间特异性蛋白质组学表型。
进行了一项创新的空间分辨率蛋白质组学研究，使用基质辅助激光解吸/电离（MALDI）成像质谱法绘制整个海马蛋白质组分布图。为此，分析了16只经脑室内注射oAβ/载体的成年雄性和雌性小鼠的大脑。使用MALDI成像RapifleXTM - MALDI - TissuetyperTM TOF/TOF质谱仪，随后进行传统串联质谱（MS/MS）以在组织上精确鉴定蛋白质。
在最初检测的234个肽段中，有34种蛋白质因处理、性别或海马位置而表现出表达水平的显著差异；并显示出显著的蛋白质 - 蛋白质相互作用（PPI），表明与LTP/LTD途径和记忆存在主要功能关系。因此，对14种与突触可塑性和/或AD相关的蛋白质进行了进一步研究，结果表明大多数蛋白质调节糖原合酶激酶 - 3β（GSK - 3β），这是一种广泛参与向LTD调节突触可塑性诱导阈值的蛋白质。相应地，发现在AD样淀粉样变性小鼠中海马GSK - 3β过度激活。
我们首次展示了背侧/腹侧海马中特定的性别依赖性突触可塑性蛋白质组变化，这些变化调节了GSK - 3β的活性。这些发现为AD早期淀粉样变性发病机制提供了新的见解，并提供了有价值的、独特的蛋白质组学表型，作为两性早期诊断和治疗的潜在生物标志物和靶点。
