Systematic phenotyping and characterization of the 5xFAD mouse model of Alzheimer’s disease

TLDR

Mouse models are essential for studying disease mechanisms and testing therapies, but for Alzheimer’s disease, selecting the appropriate model and age remains a critical challenge. The study aimed to provide a comprehensive, lifespan‑wide phenotypic characterization of the 5xFAD mouse model on a C57BL/6J background, including an 18‑month time point, to serve as a template for future late‑onset Alzheimer’s disease models. The authors performed extensive plaque, Aβ, neuropathology, neurophysiology, behavior, and glial assessments, and profiled age‑dependent transcriptional changes via bulk RNA‑seq of microdissected cortices and hippocampi, with data available through MODEL‑AD Explorer and the AD Knowledge Portal. The pipeline revealed previously unreported age‑dependent pathological features in the 5xFAD model.

Abstract

Abstract Mouse models of human diseases are invaluable tools for studying pathogenic mechanisms and testing interventions and therapeutics. For disorders such as Alzheimer’s disease in which numerous models are being generated, a challenging first step is to identify the most appropriate model and age to effectively evaluate new therapeutic approaches. Here we conducted a detailed phenotypic characterization of the 5xFAD model on a congenic C57BL/6 J strain background, across its lifespan – including a seldomly analyzed 18-month old time point to provide temporally correlated phenotyping of this model and a template for characterization of new models of LOAD as they are generated. This comprehensive analysis included quantification of plaque burden, Aβ biochemical levels, and neuropathology, neurophysiological measurements and behavioral and cognitive assessments, and evaluation of microglia, astrocytes, and neurons. Analysis of transcriptional changes was conducted using bulk-tissue generated RNA-seq data from microdissected cortices and hippocampi as a function of aging, which can be explored at the MODEL-AD Explorer and AD Knowledge Portal. This deep-phenotyping pipeline identified novel aspects of age-related pathology in the 5xFAD model.