Document Type

Article

Publication Date

10-11-2021

Publication Title

Front Aging Neurosci

Keywords

JMG

JAX Source

Front Aging Neurosci 2021 Oct 11; 13:735524

Volume

13

First Page

735524

Last Page

735524

ISSN

1663-4365

PMID

34707490

DOI

https://doi.org/10.3389/fnagi.2021.735524

Grant

AG055104, AG054345, Jackson Laboratory Startup funds

Abstract

Late-onset Alzheimer's disease (AD; LOAD) is the most common human neurodegenerative disease, however, the availability and efficacy of disease-modifying interventions is severely lacking. Despite exceptional efforts to understand disease progression via legacy amyloidogenic transgene mouse models, focus on disease translation with innovative mouse strains that better model the complexity of human AD is required to accelerate the development of future treatment modalities. LOAD within the human population is a polygenic and environmentally influenced disease with many risk factors acting in concert to produce disease processes parallel to those often muted by the early and aggressive aggregate formation in popular mouse strains. In addition to extracellular deposits of amyloid plaques and inclusions of the microtubule-associated protein tau, AD is also defined by synaptic/neuronal loss, vascular deficits, and neuroinflammation. These underlying processes need to be better defined, how the disease progresses with age, and compared to human-relevant outcomes. To create more translatable mouse models, MODEL-AD (Model Organism Development and Evaluation for Late-onset AD) groups are identifying and integrating disease-relevant, humanized gene sequences from public databases beginning with APOEε4 and Trem2*R47H, two of the most powerful risk factors present in human LOAD populations. Mice expressing endogenous, humanized APOEε4 and Trem2*R47H gene sequences were extensively aged and assayed using a multi-disciplined phenotyping approach associated with and relative to human AD pathology. Robust analytical pipelines measured behavioral, transcriptomic, metabolic, and neuropathological phenotypes in cross-sectional cohorts for progression of disease hallmarks at all life stages. In vivo PET/MRI neuroimaging revealed regional alterations in glycolytic metabolism and vascular perfusion. Transcriptional profiling by RNA-Seq of brain hemispheres identified sex and age as the main sources of variation between genotypes including age-specific enrichment of AD-related processes. Similarly, age was the strongest determinant of behavioral change. In the absence of mouse amyloid plaque formation, many of the hallmarks of AD were not observed in this strain. However, as a sensitized baseline model with many additional alleles and environmental modifications already appended, the dataset from this initial MODEL-AD strain serves an important role in establishing the individual effects and interaction between two strong genetic risk factors for LOAD in a mouse host.

Comments

We would like to acknowledge the members of the Jackson Laboratory Center for Biometrics Analysis for their efforts toward the behavioral phenotyping of these animals, the Jackson Laboratory’s Genetic Engineering Technologies Scientific Service for strain development, the Jackson Laboratory’s Clinical Assessment Services for tissue and blood chemistry analysis, and the Jackson Laboratory’s Genome Technologies group for RNA-sequencing and Nanostring assays.

This is an open-access article distributed under the terms of the Creative Commons Attribution License.

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