Aluminum chloride in Alzheimer's disease: A dual focus on molecular mechanisms and rat experimental models

Alzheimer's disease (AD) is a leading cause of dementia among middle-aged and elderly individuals globally. Animal models of AD are widely used to investigate disease mechanisms and evaluate potential treatments for disease modification. Among non-genetically modified models, aluminum (Al³⁺) induced neurotoxicity has been widely employed to mimic key features of AD, including neuroinflammation and cognitive decline. This review comprehensively elucidates current evidence on the molecular and cellular mechanisms underlying Al³⁺-induced AD-like pathology, including amyloid-β accumulation, tau protein hyperphosphorylation, oxidative stress, mitochondrial dysfunction, neuroinflammation, cholinergic system impairment, synaptic plasticity deficits, apoptosis, metal ion dyshomeostasis, and epigenetic alterations. This review critically discusses methodological variables that significantly influence experimental outcomes in Al³⁺-based models, including dosage, route of administration, exposure duration, and animal age and gender. Moreover, this review emphasizes the translational significance, advantages, and limitations of the Al³⁺-induced model by merging mechanistic insights with experimental design considerations, offering guidelines for its optimal application in AD research and treatment development.