The July issue of Alzheimer’s & Dementia spotlights progress by MODEL-AD and its work to create better models for Alzheimer’s disease research and catalyze progress in the field.
Alzheimer’s disease takes a heavy toll on patients, families and the healthcare system, and it is getting worse as the population ages. Nearly 7 million people in the United States are living with Alzheimer’s disease, and the number is projected to more than double by 2060 if no clinical interventions are developed. Sadly, to date, intensive research has yet to produce an effective preventative or treatment. The barriers to progress have been formidable, with the complexity of the disease, the mix of environmental and genetic factors contributing to it, the decades-long progression time, and difficulty in modeling it in the laboratory all playing a role.
Scientists at The Jackson Laboratory (JAX) are working to improve Alzheimer’s disease research and open new areas of exploration and discovery. The Model Organism Development and Evaluation for Late-onset Alzheimer’s Disease (MODEL-AD) Consortium, a multi-institution collaboration established to create and distribute effective mouse models for Alzheimer’s disease research, is an important part of their efforts. The JAX MODEL-AD program is led by principal investigators Professor Greg Carter, Ph.D., Professor Gareth Howell, Ph.D., and Senior Research Scientist Michael Sasner, Ph.D., who are working to develop, characterize and distribute mouse models that capture vital features of human Alzheimer’s disease better than previously possible. After years of intensive effort in partnership with Indiana University, the University of Pittsburgh, and Sage Bionetworks, much of it behind the scenes, MODEL-AD is the featured subject of the July issue of Alzheimer’s & Dementia, the journal of the Alzheimer’s Association, which will include multiple papers based on MODEL-AD research, plus another from a related program, MARMO-AD.
Tools for studying late-onset Alzheimer’s disease
For decades Alzheimer’s disease research used mice that model rare early-onset, familial versions of the disease involving mutations in the amyloid precursor protein (APP) pathway. Unfortunately, the vast majority of human patients have more complex late-onset Alzheimer’s disease (LOAD), and promising results in the APP mouse models have failed to translate to human patient populations. Specific genetic factors have been found to contribute to LOAD risk, the most prominent a version of the APOE gene known as APOE4, but the mechanisms involved are still unclear. MODEL-AD researchers therefore engineered mice that carry humanized versions of APOE4 and a mutation in the TREM2 gene known as R47H, which also carries increased LOAD risk, to create a new, LOAD-susceptible mouse model called LOAD1.
The researchers then engineered 11 other genetic variants identified by human genome-wide association studies (GWAS) as having small but significant increases in disease risk into LOAD1 mice and compared gene expression patterns in their brains with human patient groups. The study, led by Carter, examined mice at four and 12 months of age, mouse versions of early adulthood and middle age, so there will be further work with more aged mice (beyond 18 months) in the future. Nonetheless, there were important similarities between the messenger RNA (mRNA) transcripts in the mice and human patients, with the most promising variants occurring in the Abca7, Sorl1, Mthfr and Plcg2 genes. The results indicate that the mice do effectively model the molecular attributes of human LOAD and provide vital new tools for the Alzheimer’s disease research community.
Molecular and synaptic signatures of Alzheimer’s disease
The accumulation of amyloid-beta (Aß) protein plaques in the brain is a defining characteristic of LOAD in humans and has been extensively studied. While the LOAD1 mice detailed previously exhibited changes in gene expression similar to those seen in human LOAD patients, they did not exhibit Aß pathology or cognitive decline within the time frame tested. To this point therapies designed to reduce Aß or eliminate plaque buildup have proven to be minimally effective at best, but its role in disease onset and progression remains an important area of study. Therefore, in another study led by Howell and Adrian Oblak, Ph.D., of the Indiana University School of Medicine, the researchers took the LOAD1 mouse and further refined it by humanizing its Aß genetic sequence, creating what they named LOAD2 mice. They then subjected both LOAD1 and LOAD2 male and female mice to a common environmental stressor, a high fat/high sugar diet, and compared them to mice fed a control diet over an 18-month period.
The study, which provides a window into the complex genetic risk x aging x environmental factor combinations that underlie human LOAD, showed that LOAD2 mice fed the high fat/high sugar diet present with early stages of LOAD by 18 months. Interestingly, while mice of both sexes showed changes, they were larger in females, which is of note given that women have a greater risk of developing dementias than men, and twice as many women develop Alzheimer’s disease, though their longer life spans contribute to the disparity. Thorough examination and analysis revealed aspects of neuroinflammation and mild cognitive impairment in the absence of significant amyloid accumulation or prior neuropathology. The results indicate that the mice can be used to explore disease processes, independent of amyloid or tau accumulation, that likely occur very early in disease progression, providing a unique opportunity for testing potential therapeutic approaches.
A step back to step closer to humans
MODEL-AD has transformed the Alzheimer’s mouse model landscape by engineering increasingly sophisticated and relevant strains to study the disease. Another significant effort, Marmosets as Research Models for Alzheimer’s Disease (MARMO-AD), is taking a step back in terms of model sophistication, but working with a non-human primate, the marmoset, to step closer to human biology. Marmoset brains change with age in ways similar to that seen in humans, including spontaneous aggregation of Aß and hyperphosphorylated Tau that does not occur in rodent models. Stacy Rizzo, Ph.D., of the University of Pittsburgh led work that included Carter to introduce mutations in the presenilin 1 (PSEN1) gene, which causes most of the cases of familial, early-onset Alzheimer’s disease. Research with human patients with PSEN1 mutations has identified changes in the pre-symptomatic phase of the disease, including the detection of plasma Aß, showing that certain processes precede the cascade of events leading to disease. A better understanding of these early processes provides the potential to target them and prevent disease inception.
The research team successfully introduced two single-nucleotide mutations, known as C410Y and A426P, into the marmoset PSEN1 gene using CRISPR/Cas9 protocols. The specific mutations were chosen because human carriers of them are already participating in a separate study. The marmosets generated can then be studied throughout their lives and comprehensively characterized through non-invasive measures of behavior, biomarkers and molecular signatures, plus brain imaging. In the founder individuals as well as their germline offspring, the researchers found an early overproduction of an Aß subtype, Aß42, in plasma, as seen in humans before cognitive decline. They were also able to study important features of the gamma-secretase complex, which includes presenilin protein and is involved in the cleavage of many proteins, including amyloid precursor protein (APP). Gamma-secretase is therefore a potential drug target for early interventions and Alzheimer’s disease therapies. Further research with the marmoset PSEN1 mutation carriers will provide a window into the early molecular and cellular events that underlie Alzheimer’s disease and provide a critical new resource for new avenues of research and therapy discovery.
Other MODEL-AD highlights
The July issue of Alzheimer’s & Dementia includes other MODEL-AD papers as well. A research team led by Carter investigated the brain metabolomics of two mouse models, one for early-onset Alzheimer’s disease (5XFAD) and the other being LOAD1. The found notable differences in the metabolic signatures between the two models at six months, plus sex differences for several classes of metabolites. A study led by Michael Koob of the University of Minnesota and including Sasner and Carter used gene-replacement to generate mouse lines in which Alzheimer’s disease genes of interest are precisely and completely replaced in the mouse genome by their full human orthologs (conserved genes with the same function). Finally, Rizzo and Sasner provide a report on a workshop focused on improving preclinical to clinical translation in Alzheimer’s disease research. In all, the papers demonstrate the remarkable progress made by MODEL-AD, both for research findings and for resources made available for the research community. For more information about the mouse models, see https://www.model-ad.org/data-and-resources/
About the Jackson Laboratory
The Jackson Laboratory is an independent, nonprofit biomedical research institution with a National Cancer Institute-designated Cancer Center and nearly 3,000 employees in locations across the United States (Maine, Connecticut, California), Japan and China. Its mission is to discover precise genomic solutions for disease and empower the global biomedical community in the shared quest to improve human health. For more information, please visit www.jax.org.
JAX media contact: Cara McDonough, cara.mcdonough@jax.org