(701d) Negatively Charged Gold Nanoparticles Can Inhibit the Formation of Alzheimer's Disease Amyloid-β Protein Aggregates in a Mechanism-Specific Fashion

Alzheimer's disease is a progressive neurodegenerative disorder that has become increasingly prevalent in America's aging population, accounting for 70% of all diagnosed dementia cases. Current therapies for the disease allow AD patients to delay or mitigate the symptoms to improve quality of life but do not stop disease progression. At the pathological level, AD is characterized by the deposition of abnormally aggregated proteins that cause plaque formation. The accumulation of these amyloid plaques within the brain parenchyma is one of the first abnormalities and has been hypothesized to initiate AD pathogenesis; thus, our study addresses amyloid plaque formation.

The primary component of amyloid plaques found in AD is the fibrillar form of the amyloid-β protein (Aβ). During plaque formation, soluble monomeric Aβ, already present in the brain, self-assembles to form soluble aggregates that will further aggregate to create the insoluble fibrils that are deposited. Inhibition of Aβ self-assembly has emerged as a prime therapeutic strategy for this devastating disease. Aβ self-assembly involves multiple reaction intermediates related by nonlinear and interconnected nucleation and growth mechanisms, which provide multiple points for inhibitor intervention.

Nanoparticles have shown promise in biotechnology, including biological imaging and drug delivery. This study evaluates the effect of gold nanoparticles on the overall process of Aβ fibril formation, as well as on the growth of soluble aggregates that occurs later in the self-assembly pathway. Specifically, two growth mechanisms were isolated for study: elongation by monomer deposition and lateral association. The current study examines gold nanospheres ranging in size from 8 to 22 nm that display negatively charged coatings of sodium citrate or positively charged coatings of cetyltrimethylammonium bromide (CTAB) in order to determine the effects of nanoparticle size and charge. Positively charged CTAB coated nanospheres overcoated with negatively charged poly(acrylic acid) (PAA) were also studied to differentiate the effects of nanoparticle coating and charge. All sizes of both sodium citrate coated nanospheres and PAA-overcoated nanospheres inhibited Aβ fibril formation; however, CTAB-coated nanospheres exhibited little effect. These results demonstrate that while nanoparticle size and overcoating have little effect, nanoparticle charge is very important for preventing Aβ fibril formation. Furthermore, these negatively charged nanoparticles selectively reduced the rate of soluble aggregate growth by elongation, indicating that the inhibition of fibril formation occurs in a mechanism-specific fashion.