The 3xTg-AD Mouse Model: A Comprehensive Tool for Understanding Alzheimer's Disease

Alzheimer's disease (AD) is an evolving neurodegenerative disorder characterized by the presence of Amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), synaptic dysfunction, neuroinflammation, and decline in memory. Animal models are crucial resources for examining AD processes and evaluating potential treatments. Triple-transgenic mice (3xTg-AD) are genetically altered to overexpress tau, PSEN1, and APP, three genes linked to AD in humans. Both tau and amyloid pathologies are independently replicated in each model in an age-related, temporal sequence that mimics the pathophysiology of AD in humans. In addition to synaptic damage, neuroinflammation, and cognitive deficits, these mice develop intracellular Aβ accumulations at 3 to 4 months, extracellular plaques at 6 to 9 months, and NFTs at 12 months. Additionally, the model exhibits sex-dependent differences and non-cognitive symptoms like anxiety and depressive-like behavior. Recent study indicates its potential in evaluating immunotherapy, irradiation, nutraceuticals such resveratrol and lifestyle therapies for the decrease of Aβ, and tau deposition and improved cognition. Additionally, neuroimaging, and multi-omics analysis in 3xTg-AD mice provide useful biomarkers for disease monitoring. The limitations of 3xTg-AD mice include their shorter lifetime, sex-specific variations in disease and behavior and the inaccurate timing of symptom onset relative to humans. The pathological and behavioral characteristics of the 3xTg-AD mouse are well understood, but this review highlights its developing translational potential. Further studies highlight that how preclinical findings can be connected to human AD by utilizing multi-omics profiling, CRISPR-mediated genetic refinement, and integration with human iPSC-derived systems. Hence, the 3xTg-AD mouse is an effective and versatile model for studying AD processes as well as preclinical therapeutic approaches.