Wartchow Krista Mineia, Rodrigues Leticia, Dartora William Jones, Biasibetti Regina, Selistre Nicholas Guerini, Lazarian Artur, Barrios-Castellanos Carmen, Bartelo Nicholas, Gonçalves Carlos-Alberto, McIntire Laura Beth J
Brain Health Imaging Institute, Department of Radiology, Weill Cornell Medicine, New York, NY 10065, USA.
Biochemistry Post-Graduate Program, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre 90035-003, Brazil.
Int J Mol Sci. 2025 May 17;26(10):4810. doi: 10.3390/ijms26104810.
While the greatest risk factor for Alzheimer's disease (AD) is aging, women are disproportionately affected by the disease. Interestingly, the hippocampus and cerebellum exhibit gender-specific cytoarchitecture differences, which are associated with AD, despite the absence of a role in animal reproductive behavior or hormonal signaling. This study investigates the potential association of sex differences associated with AD by interrogating cerebellar and hippocampal volume in preclinical (MCI) as well as clinical phases of AD compared to cognitively normal patients (CN) and in an animal model of AD, the streptozotocin (STZ)-induced sporadic AD model. In order to investigate putative changes in cerebellum and hippocampus in a rat model of AD, we used a STZ-induced sporadic AD model at three different time points (2, 4, and 8 weeks) after surgery in male and female rats. Previous studies have reported hippocampal-dependent changes as well as sex-dependent behavioral and signaling effects in the STZ animal model of sporadic AD while our current study showed involvement of cerebellum-mediated changes. To interrogate the role of cerebellar volume in AD progression within the human context, we analyzed data available through the Alzheimer's Disease Neuroimaging Initiative (ADNI). In a cross-sectional analysis, we observed that levels of peripheral Glial Acidic Fibrillary Protein (GFAP) (astrocytic protein) were associated negatively with cerebellar and hippocampal volumes (β = -0.002, -value = 0.04; β = -6.721, -value < 0.0001) and were associated with sex specific differences in males. Our analysis identified that the effect on hippocampal volume was earlier in disease stage, reinforcing the relevance of longitudinal alterations of cerebellum and hippocampus volume over time. The STZ animal model of sporadic AD, corroborated the progressive changes in hippocampal volume and more minor and temporally delayed involvement of the cerebellum volume changes which were dependent on sex. This suggests that cerebellar involvement may be secondary to hippocampal neurodegeneration, and both regional differences were dependent on sex. Due to the association with GFAP, our findings may be due to network astrocyte connection spread regardless of primary pathology. Overall, our study uncovers a novel role for cerebellum in AD in a model and in the human context.
虽然阿尔茨海默病（AD）最大的风险因素是衰老，但女性受该疾病的影响尤为严重。有趣的是，尽管海马体和小脑在动物生殖行为或激素信号传导中不起作用，但它们表现出与AD相关的性别特异性细胞结构差异。本研究通过询问临床前期（MCI）以及AD临床阶段与认知正常患者（CN）相比的小脑和海马体积，并在AD动物模型链脲佐菌素（STZ）诱导的散发性AD模型中，研究与AD相关的性别差异的潜在关联。为了研究AD大鼠模型中小脑和海马的假定变化，我们在雄性和雌性大鼠手术后的三个不同时间点（2周、4周和8周）使用了STZ诱导的散发性AD模型。先前的研究报道了散发性AD的STZ动物模型中海马依赖性变化以及性别依赖性行为和信号传导效应，而我们目前的研究表明小脑介导的变化也参与其中。为了探讨小脑体积在人类AD进展中的作用，我们分析了通过阿尔茨海默病神经影像倡议（ADNI）获得的数据。在横断面分析中，我们观察到外周胶质纤维酸性蛋白（GFAP）（星形胶质细胞蛋白）水平与小脑和海马体积呈负相关（β = -0.002，P值 = 0.04；β = -6.721，P值 < 0.0001），并且与男性的性别特异性差异相关。我们的分析确定，对海马体积的影响在疾病阶段更早出现，这加强了小脑和海马体积随时间纵向变化的相关性。散发性AD的STZ动物模型证实了海马体积的渐进性变化以及小脑体积变化更轻微且在时间上延迟的参与，这取决于性别。这表明小脑的参与可能继发于海马神经变性，并且这两个区域差异均取决于性别。由于与GFAP的关联，我们的发现可能是由于网络星形胶质细胞连接的传播，而与原发性病理无关。总体而言，我们的研究在模型和人类背景下揭示了小脑在AD中的新作用。
