A small molecule modulating heterogeneous amyloid-β isoforms improves cognitive and pathological outcomes in acute and 5XFAD Alzheimer’s disease models
Abstract
Alzheimer’s disease (AD) is characterized by the pathological aggregation of amyloid-β (Aβ) peptides into neurotoxic assemblies. While recent antibody therapies targeting Aβ have shown clinical efficacy, they face limitations including specificity for particular Aβ species and accessibility challenges. The structural heterogeneity of Aβ isoforms, including Aβ40, Aβ42, and pyroglutamate-modified AβpE3−42, necessitates therapeutic strategies with broad-spectrum activity. The effects of YIAD-1003, a dihydropyrrolo[1,2-a]pyrazine derivative, were evaluated in vitro using Thioflavin T fluorescence assays and A11 dot blot to assess fibrillization and dissociation of preformed aggregates across Aβ40, Aβ42, and AβpE3−42. In vivo efficacy was examined in an acute Aβ42-induced AD model and in 5XFAD transgenic mice. Cognitive performance was assessed using spatial and associative memory tests. Amyloid pathology, including soluble Aβ and fibrillar deposition, and neuroinflammation markers were quantified by biochemical and histological analyses. YIAD-1003 inhibited fibril formation and promoted dissociation of preformed aggregates across multiple Aβ isoforms in vitro. In the acute model, co-administration of YIAD-1003 ameliorated Aβ42-induced memory impairment. In 5XFAD mice, oral administration improved cognitive performance, reduced plaque burden and soluble Aβ levels, and attenuated pathological alterations associated with neuroinflammation. YIAD-1003, a dihydropyrrolo[1,2-a]pyrazine…
Read the paper
Related studies
- Safety and efficacy of COVID‐19 vaccines: A systematic review and meta‐analysis of controlled and randomized clinical trials
- Accuracy Comparison between Robot-Assisted Dental Implant Placement and Static/Dynamic Computer-Assisted Implant Surgery: A Systematic Review and Meta-Analysis of In Vitro Studies
- Determinants of passive antibody efficacy in SARS-CoV-2 infection: a systematic review and meta-analysis
- Cleaning efficacy of EDDY versus ultrasonically-activated irrigation in root canals: a systematic review and meta-analysis
- Bonding Efficacy of Universal Resin Adhesives to Zirconia Substrates: Systematic Review and Meta-Analysis
- In vitro antimicrobial activity of extracts and essential oils of Cinnamomum, Salvia, and Mentha spp. against foodborne pathogens: A meta-analysis study
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.