Danica F Patton-Parfyonov, Xinming Wang, Sarah Barker, Deborah A Corey, Edwin Vázquez-Rosa, Nichele Abeyesundere, Whitney M Ward, Rebecca Darrah, Jung-A A Woo, David E Kang, Andrew A Pieper, Thomas J Kelley
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引用次数: 0
Abstract
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
期刊介绍：
The Journal of Cystic Fibrosis is the official journal of the European Cystic Fibrosis Society. The journal is devoted to promoting the research and treatment of cystic fibrosis. To this end the journal publishes original scientific articles, editorials, case reports, short communications and other information relevant to cystic fibrosis. The journal also publishes news and articles concerning the activities and policies of the ECFS as well as those of other societies related the ECFS.
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