The importance of continuing development of novel animal models of Alzheimer's disease and Alzheimer's disease and related dementias

Abstract

The development of the first mouse models of Alzheimer's disease (AD) in the mid-1990s was recognized as a significant advance in the research field. These models use transgenic overexpression of single mutations in human amyloid precursor protein (APP) or presenilin 1 (PS1). The APP mutation models like the PDAPP and the Tg2576 mice developed age-related amyloid beta (Aβ) deposition, ultimately resulting in amyloid plaques. The mice transgenic for human PS1 mutations did not demonstrate amyloid deposition; however, when crossed with an APP mutation transgenic mouse, the PS1 mutation led to more rapid deposition of amyloid and significant cognitive impairment at earlier ages than the APP mutation mice alone. These findings led to the combination of APP and PS1 mutations in single mouse models, such as the 5XFAD transgenic mice, harboring three human APP mutations and two human PS1 mutations. This mouse rapidly develops amyloid deposition, within just a few months after birth. Most recently, instead of using transgenic overexpression of mutated human genes, knock-in technologies have now introduced the human APP sequence in place of the mouse APP gene, and include one or more of the mutations associated with early-onset familial AD. These knock-in mouse models provide more physiologically relevant insights because the gene expression is under the normal regulation of the gene and does not include multiple copies of the gene of interest. Disease insights have been significantly advanced as a result of the mouse models harboring familial AD mutations in APP, PS1, and PS2. This includes leading to the development of the first successful disease-modifying therapies for AD in the form of monoclonal anti-Aβ antibodies. However, the mouse models are not complete models of AD. In fact, despite the enormous burden of amyloid deposition that occurs in these models, there is little-to-no neurodegeneration and no obvious neurofibrillary tangle (NFTs)—the other pathology, in addition to amyloid plaques, needed for diagnosis of AD. Therefore, the models are reflective of cerebral amyloidosis as opposed to frank AD. The development of models for NFTs has primarily focused on transgenic overexpression of mutant human tau; however, these mutations that are found in the mouse models of NFTs are not associated with AD, but rather frontotemporal dementia (FTD) and related tauopathies. Since the discovery of early-onset familial AD genetic mutations, many risk genes for sporadic AD have been identified including TREM2 and apolipoprotein E ε4, among many others. Also, many lifestyle risk factors for later-life AD and AD and related dementias (ADRDs) have been identified including diet, exercise, hypertension, and type 2 diabetes. With the advances in our understanding of sporadic AD and the heterogeneity of AD and ADRDs across individuals, it is clear that there is a need for the development of novel animal models of AD and ADRDs that reflect the heterogeneity, the genetic risks of sporadic disease, and the multi-morbidity in our aging population at risk of AD and ADRDs. Such animal models will also be critical for more efficacious pre-clinical drug testing for late-onset AD/ADRDs in a precision-medicine–based strategy. It was this need that led the National Institute on Aging to fund the creation of the two Model Organism Development and Evaluation for Late-onset Alzheimer's Disease (MODEL-AD) Centers: one at the University of California Irvine (UCI) and one at a collaboration between Indiana University (IU), The Jackson Laboratories (JAX), and the University of Pittsburgh (PITT). Important aspects of the MODEL-AD program include the generation of novel models; the rigorous characterization of the models by pathologic, imaging, and multi-omic approaches; the development of a robust preclinical testing pipeline; as well as full, open, data sharing through SAGE Bionetworks and sharing of the models through the JAX repository. The MODEL-AD consortium is part of a larger translational research pipeline to help speed the development of novel therapeutics for AD/ADRD that also includes the Accelerating Medicines Partnership for Alzheimer's Disease (AMP-AD), the Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD, which will be the focus of a future special issue), and early stage clinical development programs. This special issue encouraged the submission of articles from the MODEL-AD Center scientists, but also from the broad research community who may be leveraging the novel models. The goal of the special issue is to highlight the exciting advances being made in the development of model organisms for the study of AD and ADRDs, and to inform the field of the breadth of resources MODEL-AD provides to the research community, enabling improved translation of research findings to the clinic.

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