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

Abstract

Background

Intracerebral 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.

Objective

This 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.

Methods

The 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.

Results

Eighty-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.

Conclusions

The 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.