Carlsen Jasper, Fossati Silvia, Østergaard Leif, Gutiérrez-Jiménez Eugenio, Palmfeldt Johan
Research Unit for Molecular Medicine (MMF), Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark.
Alzheimer's Center at Temple (ACT) and Department of Neural Sciences, Temple University, Philadelphia, Pennsylvania, USA.
Alzheimers Dement. 2025 Apr;21(4):e70122. doi: 10.1002/alz.70122.
Cerebral amyloid angiopathy (CAA) is a hallmark of Alzheimer's disease (AD), linked to adverse effects of emerging AD treatments. We explored the molecular effects of CAA in mouse brain and evaluated how these could be prevented by two repurposed United States Food and Drug Administration (FDA) approved treatments.
Brain proteomics was performed on the Tg-SwDI genetic mouse model carrying disease causing mutations and developing AD characteristic cognitive deficits and severe CAA. Cortical and hippocampal tissues from presymptomatic male and female mice were studied.
We identify a core of dysregulated proteins across studies, including established markers of AD as well as proteins indicative of astrogliosis and negative regulators of synaptic stability and function. Two FDA approved, repurposed carbonic anhydrase inhibitors (CAIs), acetazolamide and methazolamide, were effective in preventing these molecular adaptations.
The two drugs broadly prevent proteome adaptations to the detrimental genotype and retain glutamatergic synapse proteins significantly closer to wild-type levels.
The brain proteome changes of mice with CAA are mapped. Cortical and hippocampal tissues from presymptomatic male and female mice are studied. Markers of AD, astrogliosis, and synaptic stability are dysregulated. Two CAI are effective in preventing these protein changes.
脑淀粉样血管病（CAA）是阿尔茨海默病（AD）的一个标志，与新兴AD治疗的不良反应有关。我们探究了CAA在小鼠大脑中的分子效应，并评估了美国食品药品监督管理局（FDA）批准的两种重新利用的治疗方法如何预防这些效应。
对携带致病突变并出现AD特征性认知缺陷和严重CAA的Tg-SwDI基因小鼠模型进行脑蛋白质组学研究。研究了症状前雄性和雌性小鼠的皮质和海马组织。
我们在各项研究中确定了一组失调的蛋白质核心，包括既定的AD标志物以及指示星形胶质细胞增生和突触稳定性及功能负调节因子的蛋白质。两种FDA批准的重新利用的碳酸酐酶抑制剂（CAIs），乙酰唑胺和甲醋唑胺，可有效预防这些分子适应性变化。
这两种药物广泛预防蛋白质组对有害基因型的适应性变化，并使谷氨酸能突触蛋白显著更接近野生型水平。
绘制了患有CAA的小鼠的脑蛋白质组变化图。研究了症状前雄性和雌性小鼠的皮质和海马组织。AD、星形胶质细胞增生和突触稳定性的标志物失调。两种CAI可有效预防这些蛋白质变化。
