ABSTRACT
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inheritable cause of end stage renal disease and, as of today, only a single moderately effective treatment is available for patients. Even though ADPKD research has made huge progress over the last decades, the precise disease mechanisms remain elusive. However, a wide variety of cellular and animal models have been developed to decipher the pathophysiological mechanisms and related pathways underlying the disease. As none of these models perfectly recapitulates the complexity of the human disease, the aim of this review is to give an overview of the main tools currently available to ADPKD researchers, as well as their main advantages and limitations.
Subject(s)
Polycystic Kidney, Autosomal Dominant/etiology , Polycystic Kidney, Autosomal Dominant/genetics , Polycystic Kidney, Autosomal Dominant/metabolism , Animals , Cysts/complications , Disease Models, Animal , Disease Progression , Kidney/pathology , Kidney Failure, Chronic/complications , Models, Biological , Polycystic Kidney Diseases/etiology , Polycystic Kidney Diseases/metabolism , Swine , Swine, MiniatureABSTRACT
Fipronil is an insecticide widely used for veterinary and agricultural purposes. While its insecticidal properties mostly rely on its high affinity antagonistic activity on insect γ aminobutyric acid (GABA) receptors, fipronil and its main metabolite fipronil sulfone nevertheless display non-negligible affinity for mammalian GABAA receptor. As several environmental toxicants have been shown to raise the risk of developing various neurodegenerative disorders, the aim of this study was to evaluate whether long-term low dose administration of fipronil could lead to cognitive deficiencies. Our results indicate that long-term fipronil treatment leads to behavioral perturbations in mice, indicating an accumulative effect of sustained exposure to low dose of fipronil. Although no memory impairment was observed during the course of our study, we noticed a significant hyperlocomotion behavior after 43 weeks of weekly fipronil administration, which is consistent with its direct effect on the GABAergic system.
Subject(s)
Hyperkinesis , Insecticides , Pyrazoles , Animals , Female , Hyperkinesis/chemically induced , Insecticides/toxicity , Mice , Pyrazoles/toxicity , Receptors, GABA/drug effects , gamma-Aminobutyric AcidABSTRACT
Generation of amyloid-ß peptides (Aßs) by proteolytic cleavage of the amyloid-ß protein precursor (AßPP), especially increased production of Aß42/Aß43 over Aß40, and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer's disease (AD). In familial AD (FAD), altered Aß production originates from specific mutations of AßPP or presenilins 1/2 (PS1/PS2), the catalytic subunits of γ-secretase. In sporadic AD, the origin of altered production of Aßs remains unknown. We hypothesize that the 'human chemical exposome' contains products able to favor the production of Aß42/Aß43 over Aß40 and shorter Aßs. To detect such products, we screened a library of 3500â+âcompounds in a cell-based assay for enhanced Aß42/Aß43 production. Nine pyrazole insecticides were found to induce a ß- and γ-secretase-dependent, 3-10-fold increase in the production of extracellular Aß42 in various cell lines and neurons differentiated from induced pluripotent stem cells derived from healthy and FAD patients. Immunoprecipitation/mass spectrometry analyses showed increased production of Aßs cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and shorter. Strongly supporting a direct effect on γ-secretase activity, pyrazoles shifted the cleavage pattern of another γ-secretase substrate, alcadeinα, and shifted the cleavage of AßPP by highly purified γ-secretase toward Aß42/Aß43. Focusing on fipronil, we showed that some of its metabolites, in particular the persistent fipronil sulfone, also favor the production of Aß42/Aß43 in both cell-based and cell-free systems. Fipronil administered orally to mice and rats is known to be metabolized rapidly, mostly to fipronil sulfone, which stably accumulates in adipose tissue and brain. In conclusion, several widely used pyrazole insecticides enhance the production of toxic, aggregation prone Aß42/Aß43 peptides, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in sporadic AD.
