Patton-Parfyonov Danica F, Wang Xinming, Barker Sarah, Corey Deborah A, Vázquez-Rosa Edwin, Abeyesundere Nichele, Ward Whitney M, Darrah Rebecca, Woo Jung-A A, Kang David E, Pieper Andrew A, Kelley Thomas J
Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
J Cyst Fibros. 2025 Jul;24(4):778-786. doi: 10.1016/j.jcf.2025.04.003. Epub 2025 Apr 16.
Highly effective modulator therapies (HEMT) are increasing the lifespan for many people with cystic fibrosis (pwCF), making it necessary to identify and understand CF specific age-related consequences. In this study, we examine the impact of aging on cognitive function and age-related brain pathology in a CF mouse model focusing on phospho-Tau (pTau) pathology.
Cognitive function was measured by novel object recognition and spontaneous alternation behavior tests. Hippocampal neuronal function was assessed by measuring long-term potentiation (LTP) electrophysiology, the synaptic correlate of learning and memory. Tau pathology was assessed by immunohistochemical analyses and western blot assessment of pTau levels in CF mouse brain, as well as human nasal epithelial cells isolated from pwCF.
Cognitive function declined progressively with age in Cftr (G542X/G542X) (G542X) mice, a model of CF, compared to wild-type (WT) littermate controls. LTP was also deficient in older G542X mice. Increased pTau was observed by staining and western blot analysis in the hippocampus of aged CF mice. Secondary impacts of tauopathy, including increased microglial uptake of cholesterol and reduced neuronal density were also observed. Lastly, human nasal epithelial cells from pwCF were found to display elevated pTau levels compared to non-CF controls.
Aging CF mice develop tauopathy, cognitive decline, LTP impairment, microglial activation, and neurodegeneration that is not experienced by age-matched WT littermates, a condition herein termed cystic fibrosis-related neurodegeneration (CFND). These findings suggest that pwCF may be at risk for tauopathy-related neurodegeneration and cognitive impairment with aging.
高效调节剂疗法（HEMT）正在延长许多囊性纤维化患者（pwCF）的寿命，因此有必要识别和了解囊性纤维化特有的与年龄相关的后果。在本研究中，我们在一个囊性纤维化小鼠模型中，重点关注磷酸化tau蛋白（pTau）病变，研究衰老对认知功能和与年龄相关的脑病理学的影响。
通过新颖物体识别和自发交替行为测试来测量认知功能。通过测量长时程增强（LTP）电生理学来评估海马神经元功能，LTP是学习和记忆的突触相关指标。通过免疫组织化学分析和蛋白质印迹法评估囊性纤维化小鼠脑以及从pwCF分离的人鼻上皮细胞中pTau水平，以此来评估tau病变。
与野生型（WT）同窝对照相比，囊性纤维化模型Cftr（G542X/G542X）（G542X）小鼠的认知功能随年龄增长而逐渐下降。老年G542X小鼠的LTP也存在缺陷。通过染色和蛋白质印迹分析观察到老年囊性纤维化小鼠海马中pTau增加。还观察到tau病变的继发性影响，包括小胶质细胞对胆固醇摄取增加和神经元密度降低。最后，发现与非囊性纤维化对照相比，pwCF的人鼻上皮细胞显示出pTau水平升高。
衰老的囊性纤维化小鼠会出现tau病变、认知能力下降、LTP损伤、小胶质细胞激活和神经退行性变，而年龄匹配的WT同窝小鼠则不会出现这种情况，这种情况在本文中称为囊性纤维化相关神经退行性变（CFND）。这些发现表明，pwCF可能随着年龄增长而面临tau病变相关神经退行性变和认知障碍的风险。
