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 Aβ16-21 (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 Aβ16-21 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 Aβ16-21, with no clear dose-dependent effects. Biochemical evaluation demonstrated increased levels of the anti-inflammatory cytokine IL-10 in the cortex and hippocampus after Aβ16-21 administration, while TNF-α levels remained unchanged, indicating peptide-dependent modulation of neuroimmune responses. Notably, Aβ16-21 consistently formed neurotoxic oligomeric assemblies despite its reduced length. These findings demonstrate that Aβ16-21 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, Aβ16-21 represents a valuable peptide-based tool for modeling AD-related neuropeptide dysfunction in preclinical research.