All (animal) models (of neurodegeneration) are wrong. Are they also useful?
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ABSTRACT:
SUBMITTER: Ransohoff RM
PROVIDER: S-EPMC6279414 | biostudies-literature | 2018 Dec
REPOSITORIES: biostudies-literature
Publications
All (animal) models (of neurodegeneration) are wrong. Are they also useful?
The Journal of experimental medicine 20181120 12
Richard M. Ransohoff, Entrepreneur-in-Residence at Third Rock Ventures and Visiting Scientist at Harvard Medical School, provides his personal opinion on using animal models to address current challenges and opportunities in drug development for neurodegeneration. ...[more]
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| S-EPMC7523438 | biostudies-literature
Project description:Linked articlesThis article is commented on in the editorial by Holford NHG and Anderson BJ. Why standards are useful for predicting doses. Br J Clin Pharmacol 2017; 83: 685-7. doi: 10.1111/bcp.13230 AIM: When different models for weight and age are used in paediatric pharmacokinetic studies it is difficult to compare parameters between studies or perform model-based meta-analyses. This study aimed to compare published models with the proposed standard model (allometric weight0.75 and sigmoidal maturation function).MethodsA systematic literature search was undertaken to identify published clearance (CL) reports for gentamicin and midazolam and all published models for scaling clearance in children. Each model was fitted to the CL values for gentamicin and midazolam, and the results compared with the standard model (allometric weight exponent of 0.75, along with a sigmoidal maturation function estimating the time in weeks of postmenstrual age to reach half the mature value and a shape parameter). For comparison, we also looked at allometric size models with no age effect, the influence of estimating the allometric exponent in the standard model and, for gentamicin, using a fixed allometric exponent of 0.632 as per a study on glomerular filtration rate maturation. Akaike information criteria (AIC) and visual predictive checks were used for evaluation.ResultsNo model gave an improved AIC in all age groups, but one model for gentamicin and three models for midazolam gave slightly improved global AIC fits albeit using more parameters: AIC drop (number of parameters), -4.1 (5), -9.2 (4), -10.8 (5) and -10.1 (5), respectively. The 95% confidence interval of estimated CL for all top performing models overlapped.ConclusionNo evidence to reject the standard model was found; given the benefits of standardised parameterisation, its use should therefore be recommended.
| S-EPMC5346879 | biostudies-literature
Project description:Species distribution modeling (SDM) is an essential method in ecology and conservation. SDMs are often calibrated within one country's borders, typically along a limited environmental gradient with biased and incomplete data, making the quality of these models questionable. In this study, we evaluated how adequate are national presence-only data for calibrating regional SDMs. We trained SDMs for Egyptian bat species at two different scales: only within Egypt and at a species-specific global extent. We used two modeling algorithms: Maxent and elastic net, both under the point-process modeling framework. For each modeling algorithm, we measured the congruence of the predictions of global and regional models for Egypt, assuming that the lower the congruence, the lower the appropriateness of the Egyptian dataset to describe the species' niche. We inspected the effect of incorporating predictions from global models as additional predictor ("prior") to regional models, and quantified the improvement in terms of AUC and the congruence between regional models run with and without priors. Moreover, we analyzed predictive performance improvements after correction for sampling bias at both scales. On average, predictions from global and regional models in Egypt only weakly concur. Collectively, the use of priors did not lead to much improvement: similar AUC and high congruence between regional models calibrated with and without priors. Correction for sampling bias led to higher model performance, whatever prior used, making the use of priors less pronounced. Under biased and incomplete sampling, the use of global bats data did not improve regional model performance. Without enough bias-free regional data, we cannot objectively identify the actual improvement of regional models after incorporating information from the global niche. However, we still believe in great potential for global model predictions to guide future surveys and improve regional sampling in data-poor regions.
| S-EPMC5817152 | biostudies-literature
Project description:The identification of genes linked to neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and Parkinson's disease (PD) has led to the development of animal models for studying mechanism and evaluating potential therapies. None of the transgenic models developed based on disease-associated genes have been able to fully recapitulate the behavioral and pathological features of the corresponding disease. However, there has been enormous progress made in identifying potential therapeutic targets and understanding some of the common mechanisms of neurodegeneration. In this review, we will discuss transgenic animal models for AD, ALS, HD and PD that are based on human genetic studies. All of the diseases discussed have active or complete clinical trials for experimental treatments that benefited from transgenic models of the disease.
| S-EPMC3084899 | biostudies-literature
Project description:There is a pressing need for novel diagnostic and progression biomarkers of neurodegeneration. However, the inability to determine disease duration and stage in patients with Alzheimer's disease (AD) hinders their discovery. Because animal models of disease allow us to circumvent some of these limitations, they have proven to be of paramount importance in clinical research. Due to the clear optics of the eye, the retina combined with optical coherence tomography (OCT) offers the perfect opportunity to image neurodegeneration in the retina in vivo, non-invasively, directly, quickly, and inexpensively. Based on these premises, our group has worked towards uncovering neurodegeneration-associated changes in the retina of the triple-transgenic mouse model of familial AD (3×Tg-AD). In this work, we present an overview of our work on this topic. We report on thickness variations of the retina and retinal layers/layer aggregates caused by healthy aging and AD-like conditions and discuss the implications of focusing research efforts solely on retinal thickness. We explore what other information is embedded in the OCT data, extracted based on texture analysis and deep-learning approaches, to further identify biomarkers that could be used for early detection and diagnosis. We were able to detect changes in the retina of the animal model of AD as early as 1 month of age. We also discuss our work to develop an optical coherence elastography system to measure retinal elasticity, which can be used in conjunction with conventional OCT. Finally, we discuss the potential application of these technologies in human patients and the steps needed to make OCT a helpful screening tool for the detection of neurodegeneration.
| S-EPMC11182266 | biostudies-literature
Project description:The eukaryotic cell possesses specialized pathways to turn over and degrade redundant proteins and organelles. Each pathway is unique and responsible for degradation of distinctive cytosolic material. The ubiquitin-proteasome system and autophagy (chaperone-mediated, macro, micro and organelle specific) act synergistically to maintain proteostasis. Defects in this equilibrium can be deleterious at cellular and organism level, giving rise to various disease states. Dysfunction of quality control pathways are implicated in neurodegenerative diseases and appear particularly important in Parkinson's disease and the lysosomal storage disorders. Neurodegeneration resulting from impaired degradation of ubiquitinated proteins and α-synuclein is often accompanied by mitochondrial dysfunction. Mitochondria have evolved to control a diverse number of processes, including cellular energy production, calcium signalling and apoptosis, and like every other organelle within the cell, they must be 'recycled.' Failure to do so is potentially lethal as these once indispensible organelles become destructive, leaking reactive oxygen species and activating the intrinsic cell death pathway. This process is paramount in neurons which have an absolute dependence on mitochondrial oxidative phosphorylation as they cannot up-regulate glycolysis. As such, mitochondrial bioenergetic failure can underpin neural death and neurodegenerative disease. In this review, we discuss the links between cellular quality control and neurodegenerative diseases associated with mitochondrial dysfunction, with particular attention to the emerging links between Parkinson's and Gaucher diseases in which defective quality control is a defining factor.
| S-EPMC3976615 | biostudies-literature
Project description:Dopaminergic cell death in the substantia nigra (SN) is central to Parkinson's disease (PD), but the neurodegenerative mechanisms have not been completely elucidated. Iron accumulation in dopaminergic and glial cells in the SN of PD patients may contribute to the generation of oxidative stress, protein aggregation, and neuronal death. The mechanisms involved in iron accumulation also remain unclear. Here, we describe an increase in the expression of an isoform of the divalent metal transporter 1 (DMT1/Nramp2/Slc11a2) in the SN of PD patients. Using the PD animal model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication in mice, we showed that DMT1 expression increases in the ventral mesencephalon of intoxicated animals, concomitant with iron accumulation, oxidative stress, and dopaminergic cell loss. In addition, we report that a mutation in DMT1 that impairs iron transport protects rodents against parkinsonism-inducing neurotoxins MPTP and 6-hydroxydopamine. This study supports a critical role for DMT1 in iron-mediated neurodegeneration in PD.
| S-EPMC2587621 | biostudies-literature
Project description:Of the numerous inherited diseases known to afflict the pediatric population, spinal muscular atrophy (SMA) is among the most common. It has an incidence of approximately one in 10,000 newborns and a carrier frequency of one in 50. Despite its relatively high incidence, SMA remains somewhat obscure among the many neurodegenerative diseases that affect humans. Nevertheless, the last two decades have witnessed remarkable progress in our understanding of the pathology, underlying biology and especially the molecular genetics of SMA. This has led to a genuine expectation within the scientific community that a robust treatment will be available to patients before the end of the decade. The progress made in our understanding of SMA and, therefore, towards a viable therapy for affected individuals is in large measure a consequence of the simple yet fascinating genetics of the disease. Nevertheless, important questions remain. Addressing these questions promises not only to accelerate the march towards a cure for SMA, but also to uncover novel therapies for related neurodegenerative disorders. This review discusses our current understanding of SMA, considers the challenges ahead, describes existing treatment options and highlights state-of-the-art research being conducted as a means to a better, safer and more effective treatment for the disease.
| S-EPMC3955729 | biostudies-literature
Project description:Parkinson's disease (PD) is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SN) and accumulation of intracellular α-synuclein aggregates known as Lewy bodies and Lewy neurites. Levels of polyunsaturated fatty acids (PUFAs) are reduced in the SN of PD patients and G protein-coupled receptor 40 (GPR40) serves as a receptor for PUFAs, playing a role in neurodevelopment and neurogenesis. Additionally, GPR40 is implicated in neuropathological conditions such as apoptosis and inflammation, suggesting its potential as a therapeutic target in PD. In this study, we investigated the neuroprotective effects of the GPR40 agonist, TUG469, in PD models. Our results demonstrate that TUG469 reduces neurotoxicity induced by 6-OHDA in SH-SY5Y cells. In the 6-OHDA-induced PD model, TUG469 treatment improved motor impairment, preserved dopaminergic fibers and cell bodies in the striatum (ST) or SN, and attenuated 6-OHDA-induced microgliosis and astrogliosis in the brain. Furthermore, in a PD model involving the injection of mouse ɑ-syn fibrils into the brain (mPFFs-PD model), TUG469 treatment reduced the level of phosphorylated Ser129 ɑ-synuclein and decreased microgliosis and astrogliosis in mPFFs-PD model. Our investigation also revealed that TUG469 modulates inflammasome activation, apoptosis, and autophagy in the 6-OHDA-PD model, as evidenced by RNA-seq analysis and western blotting. In summary, our findings highlight the neuroprotective effects of GPR40 agonist on dopaminergic neurons and their potential as therapeutic agents for PD. These results underscore the importance of targeting GPR40 in PD treatment, particularly in mitigating neuroinflammation and preserving neuronal integrity.
2024-08-23 | GSE275257 | GEO
Project description:ContextAccumulation of brain iron is linked to aging and protein-misfolding neurodegenerative diseases. High iron intake may influence important brain health outcomes in later life.ObjectiveThe aim of this systematic review was to examine evidence from animal and human studies of the effects of high iron intake or peripheral iron status on adult cognition, brain aging, and neurodegeneration.Data sourcesMEDLINE, Scopus, CAB Abstracts, the Cochrane Central Register of Clinical Trials, and OpenGrey databases were searched.Study selectionStudies investigating the effect of elevated iron intake at all postnatal life stages in mammalian models and humans on measures of adult brain health were included.Data extractionData were extracted and evaluated by two authors independently, with discrepancies resolved by discussion. Neurodegenerative disease diagnosis and/or behavioral/cognitive, biochemical, and brain morphologic findings were used to study the effects of iron intake or peripheral iron status on brain health. Risk of bias was assessed for animal and human studies. PRISMA guidelines for reporting systematic reviews were followed.ResultsThirty-four preclinical and 14 clinical studies were identified from database searches. Thirty-three preclinical studies provided evidence supporting an adverse effect of nutritionally relevant high iron intake in neonates on brain-health-related outcomes in adults. Human studies varied considerably in design, quality, and findings; none investigated the effects of high iron intake in neonates/infants.ConclusionsHuman studies are needed to verify whether dietary iron intake levels used in neonates/infants to prevent iron deficiency have effects on brain aging and neurodegenerative disease outcomes.
| S-EPMC5914328 | biostudies-literature