Self‐Therapeutic Nanoparticle That Alters Tau Protein and Ameliorates Tauopathy Toward a Functional Nanomedicine to Tackle Alzheimer's

Abstract

Tauopathy is a complex disorder associated at the junction of several other pathologies. Intrinsically disordered tau protein remains therapeutically challenging due to its undruggable nature and is a possible reason for monumental failure of several tau‐based therapies. Herein, nanogold remodeled tau is reported as a pseudo‐nanochaperon and shows therapeutic benefit by passive targeting in transgenic tau P301L mutant mice. Treatment with nanogold polyethylene glycol (Au‐PEG) conjugate moderately improves the learning ability of the tau P301L mice that corroborates with diminished phosphorylated tau burden. Circulating total tau level that acts in a prion fashion is significantly reduced upon Au‐PEG treatment. Similarly, a high level of tau is found in macaque monkey serum and Au‐PEG inhibits amyloidosis of Alzheimer's patients and primate's serum samples ex vivo. Addtionally, brain MRI of an old aged macaque monkey shows the decrease of grey matter, which correlates with mutual loss of grey matter upon progressive dementia as reported. Au‐PEG tunes tau and other circulating pro‐dementia factors that are present in human AD serum, by remodeling the protein and repairing aberrant proteostasis. Alteration of proteotoxic tau function by nanogold as a kinetic stablizer holds translational potential to combat socially challenging dementia.

Gold nanostructures: synthesis, properties, and neurological applications

“…535 Vimal and colleagues also reported the ability of pegylated AuNPs (B30 nm) to reduce the symptomatology in a t-P301L transgenic mouse model by inhibiting t oligomerization. 536 Recently, Shiu and collaborators developed a novel electrochemical assay to detect t-381 (an early marker of AD). An anti-t Ab and an aptamer were used to recognize the t-381 molecule, while cysteamine-stabilized AuNPs promoted the signal amplification.…”

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

“…S8, ESI †). 32 In our previous in vitro study, we found that the exogenous addition of pathological A4V SOD1 impairs motor movement of the MT cytoskeleton. 10 However, the addition of Au NPs repairs the A4SOD1-affected MT and restore MT kinesin processivity.…”

“…We have synthesized a gold nanoconjugate (Au-PEG) according to the reported literature. 32 We also used Au NPs from a commercial source. The compound was characterized using TEM and Zetasizer apparatus (Fig.…”

“…The drug particle concentration was determined using ICP-MS based on a previous report. 32 TEM analysis shows that gold nanoparticles reach the brains of littermate mice (Fig. S3, ESI †).…”

“…The gold concentration in the Au-PEG conjugate was further measured using the ICP-MS method, as reported in the previous literature. 32…”