Molecular Cobalt(II) Complexes for Tau Polymerization in Alzheimer’s Disease

Abstract

Tau is an axonal protein known to form abnormal aggregates and is the biomarker of Alzheimer’s disease. Metal-based therapeutics for inhibition of Tau aggregation is limited and rarely reported in contemporary science. Here, we report the first example of rationally designed molecular cobalt(II)-complexes for effective inhibition of Tau and disaggregation of preformed Tau fibrils. The mechanistic studies reveal that prevention of Tau aggregation by cobalt-based metal complexes (CBMCs) is concentration-dependent and Tau seldom exhibits conformational changes. Interestingly, CBMCs play dual role in causing disassembly of preformed aggregates as well as inhibition of complete Tau aggregation. Furthermore, CBMCs were nontoxic and maintained the tubulin network intact. CBMCs also prevented okadaic acid-induced toxicity in SH-SY5Y cells thus, preventing hyperphosphorylation of Tau. We believe that this unprecedented finding by the newly developed molecular complexes has a potential toward metal-based therapeutics for Alzheimer’s disease.

Phagocytosis of full-length Tau oligomers by Actin-remodeling of activated microglia

“…The human Tau40 WT protein was expressed in E. coli BL21* with 100 μg/ml of ampicillin antibiotic selection while the protein expression was induced by 0.5 mM IPTG for 3 h at 37°C as described earlier [45,46]. In brief, the bacterial cells were harvested and lysed at 15 kpsi in the Constant cell disruption system (Constant Systems Ltd.).…”

“…Spectra were measured at a bandwidth of 1 nm with a scan speed of 100 nm/min. The final spectrum depicted the average of 5 acquisitions in the range of 190 to 250 nm [46].…”

α-Linolenic acid induces clearance of Tau seed via Actin-remodeling in Microglia

“…However, PUFAs treatment reduce the production of in ammatory cytokines while exerts anti-in ammatory cytokines production as well as improves phagocytosis [13]. We prepared hTau40 aggregates in vitro with the presence of heparin as polyanionic agent, which can induce Tau aggregation [28]. The hTau40 aggregates produced in vitro were characterized for the higher molecular weight aggregates by SDS-PAGE.…”

α-Linolenic acid modulates phagocytosis of extracellular Tau and induces microglial migration

“…Conformational changes in Tau from random coiled structure to β-sheet conformation on aggregation of protein was studied using CD spectroscopy, the spectra was collected as previously mentioned in UV region [30]. The measurement was done in Jasco J-815 spectrometer, cuvette path length was 1 mm , measurement was done in range of 250 to 190 nm, and with a data pitch of 1.0 nm, and scanning speed was kept 100 nm/min .…”