Recently, the accumulation of Amyloid Beta (Aβ) in the brain has been linked to the development of Alzheimer’s disease (AD) through the formation of aggregated plaques and neurofibrillary tangles (NFTs). Although carbon nanoparticles were previously shown as having a potential to address AD, the interactions of Aβ with such nanoparticles have not been studied extensively. In this work, molecular dynamic simulations are utilized to simulate the interactions between a single atomic layer of graphene oxide (GO) and a 12-monomer Aβ fibril. These interactions are further compared to those between GO and five individual monomers of Aβ to further understand the conformational changes in Aβ as an individual monomer and as a component of the Aβ fibril. It was found that out of the 42 residues of the Aβ monomers, residues 27–42 are the most affected by the presence of GO. Furthermore, stability analysis through RMSD, conformational energies and salt bridges, along with nonbonding energy, illustrate that Aβ–Aβ interactions were successfully interrupted and dismantled by GO. Overall, the differences in the interactions between monomeric Aβ consisting of five monomers with GO, an Aβ fibril with GO, and control Aβ monomers among themselves, helped elucidate the potential that GO has to disentangle the Aβ tangles, both in case of individual monomers forming a cluster and as part of the Aβ fibril.
Keywords:amyloid beta; graphene oxide; molecular dynamics; Alzheimer’s disease
1. Introduction
According to the Center for Disease Control (CDC), Alzheimer’s disease (AD) is the most common type of dementia. According to one study, approximately 5.8 million Americans are living with AD, with this number projected to reach 14 million by the year 2060. With that being said, AD has been categorized as the 6th leading cause of death among US adults [1]. Currently, there is no cure for AD, despite the large efforts made to find one, which has fueled the need to focus on solving the cause of AD rather than its effects. Based on the current understanding, the cause of AD is the aggregation of Amyloid Beta (Aβ) monomers within the brain, specifically the neocortex of the brain [2]. Whereas the discovery of plaques as well as the presence of neuro-fibrillary tangles in the brain of persons with dementia was made by Oskar Fisher and Lois Alzheimer in the early twentieth century [3], the presence of the protein Aβ that make up the plaques was more recently found in the mid-1980s by Glenner, Masters, and Beyreuther [4,5].
Aβ has been characterized as an enhancer of memory and a modulator of mitochondrial function. Amyloid is formed by a larger protein called the Amyloid Precursor Pro-tein (APP). In the sequence of breakdowns, a toxic split can occur at Aβ-42, referring to an Aβ containing 42 amino acids. The APP plays a crucial role in neural growth and maturation, through proposed methods such as the specification of cell identity, regulating proliferation, and the formation of neural stem cells [6]. The APP is cleaved by one of the two main enzymes, Beta Secretase and Alpha Secretase. However, the selectivity of one secretase to the APP versus the other is still unknown. In a healthy brain, Alpha Secretase cleaves to the APP into sAPPalpha which protects neurons, acts as a stabilizer, and enhances memory. Conversely, Beta Secretase cleaves the APP to create sAPPbeta, which prunes synapses during neuron development. The ultimate result of Beta Secretase selectivity is Aβ-42 or Aβ-40, referring to Aβ with either 42 or 40 amino acids [6,7]. This specific strand of Aβ is particularly unfavorable. Aβ 42/40 forms clusters with itself by starting as dimers, further leading to insoluble hard aggregates that reside between the nerve cells attaching to their ends and eroding the synapse. This erosion interrupts neuronal transfer of information and the neuron’s ability to repair and metabolize [8,9]. Although the specific mechanism of folding is yet unknown, studies are being conducted to thoroughly map out the Aβ oligomer formation to target specific mechanism steps and shut down oligomerization before it happens [10]. Since that action is a premature method for hindering AD development, one possible solution to eliminating the Aβ aggregates is dissolution. Therefore, the effort of this study focuses on the effect of dissolving the formed oligomers as opposed to eliminating Aβ’s ability to oligomerize.