Targeting of β-Amyloid Peptide Fibers, a Biomarker of Alzheimer’s Disease, by Designing Specifically Functionalized Iron Oxide Nanoparticles

Alzheimer's disease (AD) is the leading cause of dementia and a major global health issue, affecting over 50 million people worldwide and projected to rise to 139 million by 2050. The disease is marked by senile plaques (SPs) formed from β-amyloid (Aβ) peptide assemblies and neurofibrillary tangles made of tau protein. Brain changes in AD begin decades before symptoms, making early diagnosis critical for potential intervention. Currently, definitive diagnosis is post-mortem, but imaging methods are being explored for early detection. Among them, MRI, due to its wide accessibility and high resolution, is promising but lacks sensitivity for SPs unless contrast agents (CAs) are used. In that context, we have designed vectorized CAs so that they allow imaging specifically SPs. Iron oxide nanoparticles (IONPs) are suitable T2 MRI CAs due to their biocompatibility, MRI properties, and easy functionalization. Indeed, functionalizing these IONPs with targeting ligands (TLs) specific to SPs is very promising to ensure an early diagnosis of AD. Thus, this study focused on developing a class of MRI CAs by coupling Amylovis─a compound developed to bind specifically to Aβ peptides─to dendron-coated IONPs. The TLs, Amylovis, were first demonstrated to have high affinity for Aβ in silico, even if coupled to dendronized IONPs. Then, dendronized IONPs were synthesized, and Amylovis was successfully coupled to them: the amount of coupled Amylovis was determined as well as the effect of this coupling on colloidal stability and relaxivity measurements of dendronized IONPs. Finally, dendronized IONPs were demonstrated to interact with Aβ1–40/42 fibers only when they bear the Amylovis TLs. The results thus showed a strong potential for these targeted nanoparticles as MRI CAs for early and specific diagnosis of AD.