Animal models with amyloid pathology are fundamental for elucidating the mechanisms underlying Alzheimer’s disease (AD). These models can be classified into toxicological, pharmacological, and transgenic categories, depending on how neurodegeneration is induced.

The 5×FAD (B6SJL) mouse line, carrying five human mutations in APP and PSEN1 (Swedish, Florida, London, M146L, L286V), represents one of the most aggressive and well-characterized transgenic models for early-onset AD. These mice exhibit intraneuronal Aβ₄₂ accumulation as early as 1.5 months, followed by extracellular plaque deposition, glial proliferation, and cortical neurodegeneration. At 4–6 months, they display marked synaptic loss (reduced synaptophysin and PSD-95), memory deficits in Y-maze and Morris water maze tests, and altered olfactory and social behaviors. Sex-dependent differences have also been reported, with females showing enhanced APP overexpression and accelerated pathology, likely estrogen-modulated. By nine months, cognitive and motor impairments are pronounced, reflecting extensive amyloidosis and neuronal loss across hippocampal and cortical regions.

The 5×FAD model, thus, integrates key neuropathological, molecular, and behavioral hallmarks of human AD, making it a powerful platform for testing phytochemical compounds and exploring mechanisms of amyloid clearance, neuroinflammation, and neuroprotection. Despite interspecies limitations, its rapid, reproducible pathology continues to provide invaluable insight into the progression and treatment of Alzheimer’s disease.