How amyloid-β peptide choice shapes neurochemical outcomes in intracerebral rat models of Alzheimer's disease: A systematic review

BackgroundIntracerebral administration of amyloid-β (Aβ) peptides remains a widely used experimental approach for modeling key neurochemical features of Alzheimer's disease (AD), including neuroinflammation, oxidative stress, and synaptic dysfunction. Among these models, Aβ1-42 and Aβ1-40 are most frequently employed. However, their effects are often treated as interchangeable despite recognized differences in aggregation behavior and biological activity.ObjectiveThis systematic review aimed to synthesize evidence on how peptide selection between Aβ1-42 and Aβ1-40 shapes neurochemical outcomes in intracerebral rat models of AD.MethodsThe review was conducted in accordance with PRISMA guidelines and registered in PROSPERO. A structured search identified in vivo rat studies using Aβ1-42 or Aβ1-40. Given methodological heterogeneity, findings were synthesized using a qualitative framework. To address potential structural confounding, stratified analyses were performed according to injection route and aggregation state.ResultsEighty-three studies met inclusion criteria (Aβ1-42 = 60; Aβ1-40 = 23). Across neurochemical domains, Aβ1-42 was more frequently associated with earlier and glial activation, increased pro-inflammatory mediators, oxidative imbalance, and synaptic alterations, often accompanied by behavioral deficits. In contrast, Aβ1-40 models showed a more variable and generally attenuated neurochemical response with greater dependence on experimental parameters. Structural analyses indicated clustering by injection route, whereas aggregation-state distribution was not statistically skewed between peptides.ConclusionsThe available evidence suggests that Aβ1-42 and Aβ1-40 should not be assumed interchangeable without explicit methodological consideration. Observed differences appear context-dependent and influenced by experimental design variables. Peptide selection with defined mechanistic objectives may enhance interpretability and translational relevance in preclinical AD research.