Potential Alzheimer's early biomarkers in a transgenic rat model and benefits of diazoxide/dibenzoylmethane co-treatment on spatial memory and AD-pathology.

Alzheimer's disease (AD) is the major form of dementia prevalent in older adults and with a high incidence in females. Identification of early biomarkers is essential for preventive intervention to delay its progression. Furthermore, due to its multifactorial nature, a multi-target approach could be therapeutically beneficial. Our studies included 4- (pre-pathology) and 11-month (mild-pathology) TgF344-AD rats, a transgenic Alzheimer's model that exhibits age-dependent AD progression. We identified two potential early biomarker genes for AD, early growth response 2 (EGR2) and histone 1H2AA (HIST1H2AA), in the hippocampus of 4-month females. Out of 17,168 genes analyzed by RNA sequencing, expression of these two genes was significantly altered in 4-month TgF344-AD rats compared to wild-type littermates. We also evaluated co-treatment with diazoxide (DZ), a potassium channel activator, and dibenzoylmethane (DIB), which inhibits eIF2α-P activity, on TgF344-AD and wild-type rats. DZ/DIB-treatment mitigated spatial memory deficits and buildup of hippocampal Aß plaques and tau PHF in 11-month TgF344-AD rats but had no effect on wild-type littermates. To our knowledge, this preclinical study is the first to report EGR2 and HIST1H2AA as potential AD biomarkers in females, and the benefits of DZ/DIB-treatment in AD. Evaluations across multiple AD-related models is warranted to corroborate our findings.

Repurposing ibudilast to mitigate Alzheimer's disease by targeting inflammation.

Alzheimer's disease is a multifactorial disease that exhibits cognitive deficits, neuronal loss, amyloid plaques, neurofibrillary tangles and neuroinflammation in the brain. Hence, a multi-target drug would improve treatment efficacy. We applied a new multi-scale predictive modelling framework that integrates machine learning with biophysics and systems pharmacology to screen drugs for Alzheimer's disease using patients' tissue samples. Our predictive modelling framework identified ibudilast as a drug with repurposing potential to treat Alzheimer's disease. Ibudilast is a multi-target drug, as it is a phosphodiesterase inhibitor and toll-like receptor 4 (TLR4) antagonist. In addition, we predict that ibudilast inhibits off-target kinases (e.g. IRAK1 and GSG2). In Japan and other Asian countries, ibudilast is approved for treating asthma and stroke due to its anti-inflammatory potential. Based on these previous studies and on our predictions, we tested for the first time the efficacy of ibudilast in Fisher transgenic 344-AD rats. This transgenic rat model is unique as it exhibits hippocampal-dependent spatial learning and memory deficits and Alzheimer's disease pathology, including hippocampal amyloid plaques, tau paired-helical filaments, neuronal loss and microgliosis, in a progressive age-dependent manner that mimics the pathology observed in Alzheimer's disease patients. Following long-term treatment with ibudilast, transgenic rats were evaluated at 11 months of age for spatial memory performance and Alzheimer's disease pathology. We demonstrate that ibudilast-treatment of transgenic rats mitigated hippocampal-dependent spatial memory deficits, as well as hippocampal (hilar subregion) amyloid plaque and tau paired-helical filament load, and microgliosis compared to untreated transgenic rat. Neuronal density analysed across all hippocampal regions was similar in ibudilast-treated transgenic compared to untreated transgenic rats. Interestingly, RNA sequencing analysis of hippocampal tissue showed that ibudilast-treatment affects gene expression levels of the TLR and ubiquitin-proteasome pathways differentially in male and female transgenic rats. Based on the TLR4 signalling pathway, our RNA sequencing data suggest that ibudilast-treatment inhibits IRAK1 activity by increasing expression of its negative regulator IRAK3, and/or by altering TRAF6 and other TLR-related ubiquitin ligase and conjugase levels. Our results support that ibudilast can serve as a repurposed drug that targets multiple pathways including TLR signalling and the ubiquitin/proteasome pathway to reduce cognitive deficits and pathology relevant to Alzheimer's disease.

Timapiprant, a prostaglandin D2 receptor antagonist, ameliorates pathology in a rat Alzheimer's model.

We investigated the relevance of the prostaglandin D2 pathway in Alzheimer's disease, because prostaglandin D2 is a major prostaglandin in the brain. Thus, its contribution to Alzheimer's disease merits attention, given the known impact of the prostaglandin E2 pathway in Alzheimer's disease. We used the TgF344-AD transgenic rat model because it exhibits age-dependent and progressive Alzheimer's disease pathology. Prostaglandin D2 levels in hippocampi of TgF344-AD and wild-type littermates were significantly higher than prostaglandin E2. Prostaglandin D2 signals through DP1 and DP2 receptors. Microglial DP1 receptors were more abundant and neuronal DP2 receptors were fewer in TgF344-AD than in wild-type rats. Expression of the major brain prostaglandin D2 synthase (lipocalin-type PGDS) was the highest among 33 genes involved in the prostaglandin D2 and prostaglandin E2 pathways. We treated a subset of rats (wild-type and TgF344-AD males) with timapiprant, a potent highly selective DP2 antagonist in development for allergic inflammation treatment. Timapiprant significantly mitigated Alzheimer's disease pathology and cognitive deficits in TgF344-AD males. Thus, selective DP2 antagonists have potential as therapeutics to treat Alzheimer's disease.

El jurado en Boyacá, 1857-1886: análisis de su contribución a la administración de justicia1 / The Jury in Boyacá, 1857-1886: Analysis of its contribution to the administration of justice / O júri em Boyacá, 1857-1886: análise de sua contribuição à administração da justiça

Resumen En el marco de los estudios actuales de Derecho criminal en Colombia, es preciso analizar y debatir la historia del jurado durante la segunda mitad del siglo XIX. Este artículo tiene por objetivo analizar su contribución a la administración de justicia en el Estado de Boyacá, a partir de la descripción de su funcionamiento, los problemas de su implementación y los discursos jurídicos y políticos de oposición a la figura. Se emplea una metodología del tipo histórico descriptivo con enfoque cualitativo, con base en el análisis de fuentes primarias oficiales, localizadas en los archivos del departamento de Boyacá y de la Biblioteca Nacional de Colombia. Se evidencia el papel de la ley frente al diseño del jurado, su estructura, ordenación y contribución en el trámite de los procesos judiciales ordinarios, que exigía la participación ciudadana en la función de administrar justicia. Se concluye que, al ser limitada, exclusiva y excluyente, no logró compaginar con la realidad social y cultural de la población boyacense de este periodo, debido a la falta de espíritu público y un verdadero entendimiento de la figura, pese a los esfuerzos de los liberales radicales por modernizar la administración de justicia en el contexto federal.

Abstract Within the framework of current criminal law studies in Colombia, it is necessary to analyze and debate the history of the jury during the second half of the 19th century. The objective of this article is to analyze its contribution to the administration of justice in the State of Boyacá, from the description of its operation, the problems of its implementation and the legal and political speeches of opposition to the figure. A methodology of the descriptive historical type with a qualitative approach is used, based on the analysis of official primary sources, located in the archives of the Department of Boyacá and the National Library of Colombia. Evidencing the role of the law against the design of the jury, its structure, ordination and contribution in the processing of ordinary judicial processes, which required citizen participation in the function of administering justice. Concluding that, being limited, exclusive and excluding, I can not reconcile with the social and cultural reality of the Boyacá population of this period, due to the lack of public spirit and a true understanding of the figure, despite the efforts of the liberals radicals to modernize the administration of justice in the federal context.

Resumo No marco dos estudos atuais do Direito criminal na Colômbia, é preciso analisar e debater a história do júri durante a segunda metade do século XIX. Este artigo tem como objetivo analisar a contribuição desse à administração da justiça no Estado de Boyacá, a partir da descrição de seu funcionamento, os problemas na sua implementação e os discursos jurídicos e políticos de oposição à figura. Se utiliza uma metodologia de tipo histórico descritivo de abordagem qualitativa, com base na análise de fontes primárias oficiais, localizadas nos arquivos do estado de Boyacá e da Biblioteca Nacional da Colômbia. Evidencia-se o papel da lei diante da consolidação do júri, sua estrutura, ordenação e contribuição no trâmite dos processos judiciais ordinários, que exigia a participação cidadã na função de administrar justiça. Conclui-se que, ao ser limitada, exclusiva e excludente, não conseguiu compaginar com a realidade social e cultural da população boyacense desse período, dada a falta de espírito público e de um verdadeiro entendimento da figura, apesar dos esforços dos liberais radicais por modernizar a administração da justiça no contexto federal.