Nanoparticle Assisted Regulation of Nucleation Pathway of Amyloid Tetramer and Inhibition of Their Fibrillation Kinetics.

Low molecular weight (LMW) soluble amyloid oligomers have been established as primary neurotoxic species that play a key role in Alzheimer's disease etiology. However, detection and separation of such energetically unfavored, metastable species are extremely challenging due to their short lifetime and dynamic nature. In this work, the aggregation of amyloid beta has been precisely regulated to produce their tetramer, the most toxic species among the pool of LMW amyloid oligomer since this tetramer is of key scientific importance and its inhibition could offer insights into developing early phase therapeutics for amyloidosis. The in-depth structural characterization as well as the regulation of these isolated tetramers has also been achieved for the first time in an in vitro model using nontoxic novel N -methyl d-aspartic acid (NMDA) functionalized gold nanoparticle (GNP-NMDA) that interacts specifically through electrostatic interactions to form stable GNP-amyloid coaggregates and directing the nucleation toward secondary nucleation pathway rapidly unlike in control experiment where nucleation proceeds mainly via primary nucleation pathway. NMDA receptor modulators are approved by the Food and Drug Administration (FDA) as an existing treatment for moderate to severe stage Alzheimer's Disease (AD); hence, GNP decorated with NMDA offers a promising strategy toward AD. This remarkable strategy for the inhibition of the most neurotoxic LMW tetramer form of the soluble amyloid oligomers toward a nontoxic aggregation path by GNP-NMDA presents a rationale target for drug designing and to develop early stage therapeutics against several neurodegenerative diseases.