ABSTRACT
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the formation of toxic amyloid-ß (Aß) oligomers and plaques. Considering that Aß misfolding and aggregation precedes the progressive development of cognitive impairment in AD, investigating a therapeutic means by clearance of pre-existing Aß aggregates shows promise as a viable disease-modifying treatment. Here, we report that a small molecule, necrostatin-1 (Nec-1), reduces Aß aggregates back to non-toxic monomers in vitro and in vivo. Intravenous administration of Nec-1 reduced the levels of Aß plaques in the brains of aged APP/PS1 double transgenic mice. In addition, Nec-1 exhibited therapeutic effects against Aß aggregates by inhibiting Aß-induced brain cell death in neuronal and microglial cell lines. Nec-1 also showed anti-apoptotic and anti-necroptotic effects in the cortex of aged APP/PS1 mice by reducing levels of phosphorylated-RIPK3 and Bax and increasing the levels of Bcl-2. According to our data in vitro and in silico, the methyl group of the amine in the 2-thioxo-4-imidazolidinone is the key moiety of Nec-1 that directs its activity against aggregated Aß. Given that the accumulation of Aß aggregates is an important hallmark of AD, our studies provide strong evidence that Nec-1 may serve a key role in the development of AD treatment.
Subject(s)
Aging/metabolism , Amyloid beta-Protein Precursor/metabolism , Amyloid/metabolism , Brain/metabolism , Imidazoles/pharmacology , Indoles/pharmacology , Presenilin-1/metabolism , Small Molecule Libraries/pharmacology , Animals , Brain/drug effects , Cell Death/drug effects , Cell Line , Humans , Imidazoles/chemistry , Indoles/chemistry , Male , Mice, Transgenic , Molecular Docking Simulation , Plaque, Amyloid/metabolism , Plaque, Amyloid/pathology , Protein Aggregates/drug effectsABSTRACT
Understanding the physiological implications of caging conditions for mice is crucial in improving the replicability and reliability of animal research. Individual caging of mice is known to alter mouse psychology, such as triggering depression-like symptoms in mice, suggesting that caging conditions could have negative effects on mice. Therefore, we hypothesized that individual caging could affect the physical composition of outbred mice. To investigate this, dual X-ray absorptiometry (DXA) was used to compare the mass, bone mineral content (BMC), bone mineral density (BMD), lean tissue percentage and fat tissue percentage between group and individual caged mice. We also conducted open field test to compare mouse activities in different caging conditions. Our results showed significantly reduced BMD and lean tissue percentage and significantly increased fat tissue percentage in individually-caged male mice. Furthermore, there were no differences in body mass and activity between the grouped and individual mice, suggesting that these physical alterations were not induced by group-related activity. In this study, we conclude that individual caging could alter the body composition of mice without affecting external morphology.
