Development of Multifunctional Gold Nanoparticles for Diagnosis and Therapy of Alzheimer'S Disease

Abstract

Alzheimer's disease (AD) is an incurable neurodegenerative disease, leading to cognitive impairment and neuronal loss. Recent clinical trials suggest the necessity of diagnosing AD at an early stage for effective therapy. Despite significant progress in imaging technologies, early diagnosis of AD remains a major challenge. This study presents a novel diagnostic strategy for molecular computed tomography (CT) imaging of AD-associated amyloid β (Aβ) aggregates at an early stage of AD.

We have recently reported on a self-assembled cyclic D,L-α-peptide (CP) that interacts with early forms of Aβ species and inhibits their further aggregation and toxicity. These studies also suggested that CP acts as a conformational inhibitor to interact also with Parkinson’s disease associated α-syn and tau-derived PHF6 peptide and prevent their aggregation and toxicity.

To develop a diagnostic probe that can detect AD in early stages of pathogenesis, we have conjugated CT-detectable and BBB permeable gold nanoparticles (GNPs) to CP that selectively targets early Aβ oligomers. The in-vitro results, including thioflavin T, TEM and cell toxicity experiments demonstrated that the conjugated GNPs preserved the antiamyloidogenic properties of CP to bind and inhibit Aβ aggregation, and decrease its toxicity to neuron-like cells. Moreover, the conjugated GNPs sensitively and specifically bind diffusible Aβ species in brain slices derived from 5xFAD transgenic AD mouse model and disassemble the existing Aβ plaques. In our in-vivo experiments, the particles effectively penetrated the brains of the AD mice as well as of the WT animals. However, 12 hours after their i.v. administration, the particles could be detected by CT only in the brains of the AD mice. Using this technology, AD was diagnosed in symptom-free AD mice as early as 2-4 month. Our studies suggest that targeting the common structural conformation of amyloids may be a promising approach for developing new theranostics for AD.