Remodeling Tau and Prion Proteins Using Nanochaperons

Abstract

There is increasing evidence that tau protein behaves in a prion‐like manner in tauopathy. The stabilization of tau protein using a small molecular compound can limit tauopathy associated morbidity that advances with ageing. Here, a lab‐on‐a‐chip experiment is reported, where gold citrate nanoparticles (5 nm, AuNPs) can remodel mutant tau protein (P301L) and prion, thus resolving the mutant tau‐ and prion‐mediated impairment of kinesin cargo transport on microtubules. It is found that tau protein is overexpressed in Alzheimer's disease (AD) patient serum samples and the tau conformational change can also be affected in human serum samples of AD when treated with AuNPs ex vivo. Similarly, AuNPs reorganizing the prion protein and inducing conformational changes of prions in AD serum have been observed, while having no effect on alpha‐synuclein in Parkinson patient serum. The mapping of AD serum mediated traffic jams, using particle tracking and mean square displacement analysis, and the observed recovery of uninterrupted processive motor functions by AuNP treatment show that kinesin cargo assays might be a useful method for future ex vivo validation of a targeted therapy against tauopathy before administration, a viable option to combat various neurodegenerative disorders arising from the susceptibility of amyloidogenic proteins toward aggregation.

In vivoandin silicoinvestigations of the pegylated gold nanoparticle treatment of amyotrophic lateral sclerosis in mice

“…[41][42][43] We have studied a few proteins in the past, such as tau proteins, prions, SOD1, and a-synuclein, and we have found that Au NPs can remodel their function. 11,43,44 Therefore, this ability of Au NPs to bind to multiple proteins can be viewed as a bonus when encountering disease heterogeneity, such as in the case of ALS; however, concern remains with regards to binding with non-targets with unforeseen side effects. We could only achieve a suboptimal dose of Au-PEG, because Au NPs can be concentrated to a certain extent for therapeutic dosing in animals but beyond that, macromolecular particles tend to aggregate, thereby causing therapeutic loss.…”

“…In addition, in a series of previous reports, we found that Au NPs can act as pseudo nanochaperons and remodel intrinsically misfolded proteins, such as tau proteins and prions. 11 Over the decades gold nanoparticles (Au NPs) have shown great advantages during use in clinical diagnosis or the treatment of various diseases. Au NPs can successfully cross the blood-brain barrier (BBB) and bloodspinal cord barrier (BSCB), target cells or subcellular units, and modulate the activity of neuronal tissue (DOI: https://doi.org/10.…”

Nanomodulators That Target Alzheimer’s Disease: A Review

“…In contrast, biomimetic nanoparticles is an emerging class of functional nanomaterial that can be camouflaged with biological systems. 104,125,129,[131][132][133][134][136][137][138]149 Table 7 lists the function and composition of some biomimetic nanoparticles designed for treating AD. 104,131,132,134 For example, "shell"-like active cell membrane (red blood cell membrane, platelet membrane, lymphocyte membrane, etc.…”

“…Recently, Bhattacharyya et al have accounted that in the presence of citrate capped gold nanoparticle (AuNP) of 5 nm size, mutant tau protein (P301L) and mutant prion can refold in a native form with retention of biological function. 132 More importantly, gold nanochaperone can resolve the mutant tauand mutant prion-mediated impairment of kinesin cargo transport on microtubules. The immune dot blot assays of tau and prion protein using human blood serum of normal and AD patients have depicted that AuNP triggers the change in secondary structure of the mutant tau and prion protein in AD serum.…”

“…The use of exogenous material as a scaffold, early recognition by the immune system, and rapid clearance through the kidney and liver restrict the clinical application of conventional nanoparticles. In contrast, biomimetic nanoparticles is an emerging class of functional nanomaterial that can be camouflaged with biological systems. ,,,− ,− , Table lists the function and composition of some biomimetic nanoparticles designed for treating AD. ,,, For example, “shell”-like active cell membrane (red blood cell membrane, platelet membrane, lymphocyte membrane, etc. )-coated “core”-like nanoparticles are a group of a biomimetic nanoparticle.…”