Ng Ding Quan, Hudson Casey, Nguyen Tracy, Gupta Sukesh Kumar, Koh Yong Qin, Acharya Munjal M, Chan Alexandre
Department of Clinical Pharmacy Practice, School of Pharmacy & Pharmaceutical Sciences, University of California Irvine, Irvine, CA, USA.
Department of Anatomy & Neurobiology, School of Medicine, University of California Irvine, Irvine, CA, USA.
Neurotherapeutics. 2025 Jan;22(1):e00480. doi: 10.1016/j.neurot.2024.e00480. Epub 2024 Nov 7.
Dynamin-1 (DNM1) is crucial for synaptic activity, neurotransmission, and associative memory, positioning it as a potential biomarker of cancer-related cognitive impairment (CRCI), a neurological consequence of cancer treatment characterized by memory loss, poor concentration, and impaired executive function. Through a stepwise approach, this study investigated the role of DNM1 in CRCI pathogenesis, incorporating both human data and animal models. The human study recruited newly diagnosed, chemotherapy-naïve adolescent and young adult cancer and non-cancer controls to complete a cognitive instrument (FACT-Cog) and blood draws for up to three time points. Following that, a syngeneic young-adult WT (C57BL/6) female mouse model of breast cancer chemobrain was developed to study DNM1 expression in the hippocampus. Samples from eighty-six participants with 30 adolescent and young adult (AYA) cancer and 56 non-cancer participants were analyzed. DNM1 levels were 32 % lower (P = 0.041) among cancer participants compared to non-cancer prior to treatment. After receiving cytotoxic treatment, cognitively impaired cancer patients were found to have 46 % lower DNM1 levels than those without impairment (P = 0.049). In murine breast cancer-bearing mice receiving chemotherapy, we found a greater than 40 % decline (P < 0.0001) in DNM1 immunoreactivity in the hippocampal CA1 and CA3 subregions concurrent with a deterioration in spatial recognition memory (P < 0.02), compared to control mice without exposure to cancer and chemotherapy. Consistently observed in both human and animal studies, the downregulation of DNM1 is linked with the onset of CRCI. DNM1 might be a biomarker and therapeutic target for CRCI.
发动蛋白-1(DNM1)对突触活动、神经传递和联想记忆至关重要,这使其成为癌症相关认知障碍(CRCI)的潜在生物标志物,CRCI是癌症治疗的一种神经学后果,其特征为记忆力减退、注意力不集中和执行功能受损。通过逐步研究方法,本研究调查了DNM1在CRCI发病机制中的作用,纳入了人类数据和动物模型。人类研究招募了新诊断的、未接受过化疗的青少年和青年癌症患者以及非癌症对照者,以完成一项认知测试工具(FACT-Cog)并在多达三个时间点进行血液采集。在此之后,建立了同基因的青年成年野生型(C57BL/6)雌性乳腺癌化疗脑小鼠模型来研究海马体中DNM1的表达。对86名参与者的样本进行了分析,其中包括30名青少年和青年癌症患者以及56名非癌症参与者。与治疗前的非癌症参与者相比,癌症参与者的DNM1水平低32%(P = 0.041)。在接受细胞毒性治疗后,发现认知受损的癌症患者的DNM1水平比未受损患者低46%(P = 0.049)。在接受化疗的荷瘤小鼠中,我们发现与未接触癌症和化疗的对照小鼠相比,海马体CA1和CA3亚区的DNM1免疫反应性下降超过40%(P < 0.0001),同时空间识别记忆能力恶化(P < 0.02)。在人类和动物研究中均一致观察到,DNM1的下调与CRCI的发病有关。DNM1可能是CRCI的生物标志物和治疗靶点。