Improving preclinical to clinical translation in Alzheimer\u27s disease research.

Introduction: Preclinical testing in animal models is a critical component of the drug discovery and development process. While hundreds of interventions have demonstrated preclinical efficacy for ameliorating cognitive impairments in animal models, none have confirmed efficacy in Alzheimer\u27s disease (AD) clinical trials. Critically this lack of translation to the clinic points in part to issues with the animal models, the preclinical assays used, and lack of scientific rigor and reproducibility during execution. In an effort to improve this translation, the Preclinical Testing Core (PTC) of the Model Organism Development and Evaluation for Late-onset AD (MODEL-AD) consortium has established a rigorous screening strategy with go/no-go decision points that permits unbiased assessments of therapeutic agents. Methods: An initial screen evaluates drug stability, formulation, and pharmacokinetics (PK) to confirm appreciable brain exposure in the disease model at the pathologically relevant ages, followed by pharmacodynamics (PD) and predictive PK/PD modeling to inform the dose regimen for long-term studies. The secondary screen evaluates target engagement and disease modifying activity using non-invasive positron emission tomography/magnetic resonance imaging (PET/MRI). Provided the compound meets its go criteria for these endpoints, evaluation for efficacy on behavioral endpoints are conducted. Results: Validation of this pipeline using tool compounds revealed the importance of critical quality control (QC) steps that researchers need to be aware of when executing preclinical studies. These include confirmation of the active pharmaceutical ingredient and at the precise concentration expected; and an experimental design that is well powered and in line with the Animal Research Reporting of In vivo Experiments (ARRIVE) guidelines. Discussion: Taken together our experience executing a rigorous screening strategy with QC checkpoints provides insight to the challenges of conducting translational studies in animal models. The PTC pipeline is a National Institute on Aging (NIA)-supported resource accessible to the research community for investigators to nominate compounds for testing (https://stopadportal.synapse.org/), and these resources will ultimately enable better translational studies to be conducted

A novel systems biology approach to evaluate mouse models of late-onset Alzheimer\u27s disease.

BACKGROUND: Late-onset Alzheimer\u27s disease (LOAD) is the most common form of dementia worldwide. To date, animal models of Alzheimer\u27s have focused on rare familial mutations, due to a lack of frank neuropathology from models based on common disease genes. Recent multi-cohort studies of postmortem human brain transcriptomes have identified a set of 30 gene co-expression modules associated with LOAD, providing a molecular catalog of relevant endophenotypes. RESULTS: This resource enables precise gene-based alignment between new animal models and human molecular signatures of disease. Here, we describe a new resource to efficiently screen mouse models for LOAD relevance. A new NanoString nCounter® Mouse AD panel was designed to correlate key human disease processes and pathways with mRNA from mouse brains. Analysis of the 5xFAD mouse, a widely used amyloid pathology model, and three mouse models based on LOAD genetics carrying APOE4 and TREM2*R47H alleles demonstrated overlaps with distinct human AD modules that, in turn, were functionally enriched in key disease-associated pathways. Comprehensive comparison with full transcriptome data from same-sample RNA-Seq showed strong correlation between gene expression changes independent of experimental platform. CONCLUSIONS: Taken together, we show that the nCounter Mouse AD panel offers a rapid, cost-effective and highly reproducible approach to assess disease relevance of potential LOAD mouse models

Model organism development and evaluation for late‐onset Alzheimer's disease: MODEL‐AD

Alzheimer's disease (AD) is a major cause of dementia, disability, and death in the elderly. Despite recent advances in our understanding of the basic biological mechanisms underlying AD, we do not know how to prevent it, nor do we have an approved disease‐modifying intervention. Both are essential to slow or stop the growth in dementia prevalence. While our current animal models of AD have provided novel insights into AD disease mechanisms, thus far, they have not been successfully used to predict the effectiveness of therapies that have moved into AD clinical trials. The Model Organism Development and Evaluation for Late‐onset Alzheimer's Disease (MODEL‐AD; www.model-ad.org) Consortium was established to maximize human datasets to identify putative variants, genes, and biomarkers for AD; to generate, characterize, and validate the next generation of mouse models of AD; and to develop a preclinical testing pipeline. MODEL‐AD is a collaboration among Indiana University (IU); The Jackson Laboratory (JAX); University of Pittsburgh School of Medicine (Pitt); Sage BioNetworks (Sage); and the University of California, Irvine (UCI) that will generate new AD modeling processes and pipelines, data resources, research results, standardized protocols, and models that will be shared through JAX's and Sage's proven dissemination pipelines with the National Institute on Aging–supported AD Centers, academic and medical research centers, research institutions, and the pharmaceutical industry worldwide

A novel systems biology approach to evaluate mouse models of late-onset Alzheimer’s disease

Background Late-onset Alzheimer’s disease (LOAD) is the most common form of dementia worldwide. To date, animal models of Alzheimer’s have focused on rare familial mutations, due to a lack of frank neuropathology from models based on common disease genes. Recent multi-cohort studies of postmortem human brain transcriptomes have identified a set of 30 gene co-expression modules associated with LOAD, providing a molecular catalog of relevant endophenotypes. Results This resource enables precise gene-based alignment between new animal models and human molecular signatures of disease. Here, we describe a new resource to efficiently screen mouse models for LOAD relevance. A new NanoString nCounter® Mouse AD panel was designed to correlate key human disease processes and pathways with mRNA from mouse brains. Analysis of the 5xFAD mouse, a widely used amyloid pathology model, and three mouse models based on LOAD genetics carrying APOE4 and TREM2*R47H alleles demonstrated overlaps with distinct human AD modules that, in turn, were functionally enriched in key disease-associated pathways. Comprehensive comparison with full transcriptome data from same-sample RNA-Seq showed strong correlation between gene expression changes independent of experimental platform. Conclusions Taken together, we show that the nCounter Mouse AD panel offers a rapid, cost-effective and highly reproducible approach to assess disease relevance of potential LOAD mouse models. Supplementary information Supplementary information accompanies this paper at 10.1186/s13024-020-00412-5

Model organism development and evaluation for late-onset Alzheimer's disease: MODEL-AD.

Alzheimer's disease (AD) is a major cause of dementia, disability, and death in the elderly. Despite recent advances in our understanding of the basic biological mechanisms underlying AD, we do not know how to prevent it, nor do we have an approved disease-modifying intervention. Both are essential to slow or stop the growth in dementia prevalence. While our current animal models of AD have provided novel insights into AD disease mechanisms, thus far, they have not been successfully used to predict the effectiveness of therapies that have moved into AD clinical trials. The Model Organism Development and Evaluation for Late-onset Alzheimer's Disease (MODEL-AD; www.model-ad.org) Consortium was established to maximize human datasets to identify putative variants, genes, and biomarkers for AD; to generate, characterize, and validate the next generation of mouse models of AD; and to develop a preclinical testing pipeline. MODEL-AD is a collaboration among Indiana University (IU); The Jackson Laboratory (JAX); University of Pittsburgh School of Medicine (Pitt); Sage BioNetworks (Sage); and the University of California, Irvine (UCI) that will generate new AD modeling processes and pipelines, data resources, research results, standardized protocols, and models that will be shared through JAX's and Sage's proven dissemination pipelines with the National Institute on Aging-supported AD Centers, academic and medical research centers, research institutions, and the pharmaceutical industry worldwide