A novel synthetic peptide impairs spatial working memory in mice: A promising tool for dementia-related neurotoxicity animal models studies

The rapid aging of the global population is contributing to a sharp increase in dementia cases, with Alzheimer's disease (AD) accounting for the majority of diagnoses. The most widely accepted theory explaining AD pathogenesis is the amyloid cascade hypothesis, which implicates the accumulation of amyloid-β (Aβ) peptides, particularly the Aβ1–42 isoform, as a key pathogenic event. Oligomeric forms of Aβ1–42 act as bioactive neurotoxic peptides, disrupting synaptic function and neuronal homeostasis. Despite its frequent use in animal models, Aβ1–42 presents challenges due to its high cost and complex handling. In this study, we applied bioinformatic and structural approaches to identify a minimal peptide motif within Aβ1–42 capable of reproducing its neurobiological effects. We designed and evaluated the peptide fragment Aβ 16–21 (KLVFFA), which corresponds to the hydropHobic core of Aβ1–42 and is a critical determinant of peptide aggregation and bioactivity. We assessed the cognitive and biochemical effects of intracerebroventricular administration of Aβ 16–21 in mice and compared its impact to that of Aβ1–42. Behavioral testing revealed significant deficits in both working and reference memory in animals treated with either Aβ1–42 or Aβ 16–21 , with no clear dose-dependent effects. Biochemical evaluation demonstrated increased levels of the anti-inflammatory cytokine IL-10 in the cortex and hippocampus after Aβ 16–21 administration, while TNF-α levels remained unchanged, indicating peptide-dependent modulation of neuroimmune responses. Notably, Aβ 16–21 consistently formed neurotoxic oligomeric assemblies despite its reduced length. These findings demonstrate that Aβ 16–21 retains key neurotoxic and immunomodulatory properties of full-length Aβ1–42, supporting its use as a biologically relevant minimal neuroactive peptide. Due to its structural simplicity, reproducibility, lower cost, and experimental accessibility, Aβ 16–21 represents a valuable peptide-based tool for modeling AD-related neuropeptide dysfunction in preclinical research. • Aβ16-21 mimics key neurotoxic effects of full-length Aβ1-42 in mice. • Both peptides induced working and reference memory impairments. • Aβ16-21 increased cortical and hippocampal IL-10 without altering TNF-α. • Short peptide forms toxic oligomers despite no dose-dependent effects. • Aβ16-21 offers a low-cost, accessible peptide as a tool for Alzheimer’s disease research.