Behavioral Paradigms and Methodological Variability in Aluminum Chloride-Induced Rat Models of Alzheimer's Disease: A...

Aluminum chloride (AlCl₃)-induced rat models are widely used to investigate Alzheimer-like neurodegeneration, yet substantial methodological variability limits cross-study comparability. A structured synthesis focused specifically on the methodological architecture of these models, including dose, exposure duration, route of administration, and behavioral assessment, remains lacking. This review aimed to synthesize the behavioral paradigms used to assess learning and memory in rat models of aluminum chloride-induced Alzheimer's disease, with particular emphasis on dose, duration, and route of administration. A structured narrative review incorporating systematic elements was conducted following PRISMA-informed procedures using PubMed, Web of Science, and Scopus. The reviewed literature showed a predominance of oral administration, low-to-moderate AlCl₃ doses and subchronic exposure durations, most commonly 31-60 days. Behavioral assessment was dominated by hippocampal-dependent paradigms, particularly the Morris water maze and Y-maze. Across studies, AlCl₃ exposure was associated with multidomain behavioral impairment accompanied by consistent hippocampal and cortical histopathological abnormalities and convergent biochemical and molecular changes, including cholinergic dysfunction, oxidative stress, neuroinflammation, and amyloid- and tau-related alterations. Overall, the available literature does not support a standardized experimental protocol or a clear overall dose-effect or duration-effect relationship. Greater harmonization of study design is needed to improve reproducibility and translational relevance.