RESUMEN
Primary ciliary dyskinesia (PCD) is a rare heterogenic genetic disorder associated with perturbed biogenesis or function of motile cilia. Motile cilia dysfunction results in diminished mucociliary clearance (MCC) of pathogens in the respiratory tract and chronic airway inflammation and infections successively causing progressive lung damage. Current approaches to treat PCD are symptomatic, only, indicating an urgent need for curative therapeutic options. Here, we developed an in vitro model for PCD based on human induced pluripotent stem cell (hiPSC)-derived airway epithelium in Air-Liquid-Interface cultures. Applying transmission electron microscopy, immunofluorescence staining, ciliary beat frequency, and mucociliary transport measurements, we could demonstrate that ciliated respiratory epithelia cells derived from two PCD patient-specific hiPSC lines carrying mutations in DNAH5 and NME5, respectively, recapitulate the respective diseased phenotype on a molecular, structural and functional level.
Asunto(s)
Trastornos de la Motilidad Ciliar , Células Madre Pluripotentes Inducidas , Humanos , Sistema Respiratorio , Epitelio , Trastornos de la Motilidad Ciliar/genética , Fenotipo , Nucleósido Difosfato Quinasas NM23RESUMEN
AIMS: Amyloid precursor protein (APP) ð½-C-terminal fragment (ð½CTF) may have a neurotoxic role in Alzheimer's disease (AD). ð½CTF accumulates in the brains of patients with sporadic (SAD) and genetic forms of AD. Synapses degenerate early during the pathogenesis of AD. We studied whether the ð½CTF accumulates in synapses in SAD, autosomal dominant AD (ADAD) and Down syndrome (DS). METHODS: We used array tomography to determine APP at synapses in human AD tissue. We measured ð½CTF, Að½40, Að½42 and phosphorylated tau181 (p-tau181) concentrations in brain homogenates and synaptosomes of frontal and temporal cortex of SAD, ADAD, DS and controls. RESULTS: APP colocalised with pre- and post-synaptic markers in human AD brains. APP ð½CTF was enriched in AD synaptosomes. CONCLUSIONS: We demonstrate that ð½CTF accumulates in synapses in SAD, ADAD and DS. This finding might suggest a role for ð½CTF in synapse degeneration. Therapies aimed at mitigating ð½CTF accumulation could be potentially beneficial in AD.