Protein aggregation and neurodegenerative disease: Structural outlook for the novel therapeutics

Abstract

Before the controversial approval of humanized monoclonal antibody lecanemab, which binds to the soluble amyloid‐β protofibrils, all the treatments available earlier, for Alzheimer's disease (AD) were symptomatic. The researchers are still struggling to find a breakthrough in AD therapeutic medicine, which is partially attributable to lack in understanding of the structural information associated with the intrinsically disordered proteins and amyloids. One of the major challenges in this area of research is to understand the structural diversity of intrinsically disordered proteins under in vitro conditions. Therefore, in this review, we have summarized the in vitro applications of biophysical methods, which are aimed to shed some light on the heterogeneity, pathogenicity, structures and mechanisms of the intrinsically disordered protein aggregates associated with proteinopathies including AD. This review will also rationalize some of the strategies in modulating disease‐relevant pathogenic protein entities by small molecules using structural biology approaches and biophysical characterization. We have also highlighted tools and techniques to simulate the in vivo conditions for native and cytotoxic tau/amyloids assemblies, urge new chemical approaches to replicate tau/amyloids assemblies similar to those in vivo conditions, in addition to designing novel potential drugs.

Exploring Tau Fibril-Disaggregating and Antioxidating Molecules Binding to Membrane-Bound Amyloid Oligomers Using Machine Learning-Enhanced Docking and Molecular Dynamics

“…These highly ordered tau fibrils are cytotoxic and sources of oxidative stress in AD development [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. However, recent in vivo and in vitro studies [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ] strongly suggest that the smaller, less-ordered membrane-bound tau oligomers are also cytotoxic to neurons in early AD pathogenesis. This is pertinent considering that patients with AD appear symptom-free in preclinical stages, although neurotoxicity is present in the brain [ 1 ].…”

“…Notably, a higher incidence of AD is found in patients with type 2 diabetes compared to individuals without comorbidities: 81% of people with AD also have type 2 diabetes or abnormal fasting glucose levels [ 35 ]. To date, tau fibrils have been the primary therapeutic target in AD, and virtual drug discovery studies have mostly focused on developing small molecules for tau fibril disaggregation and elimination of reactive oxygen species or antioxidation [ 6 , 15 , 24 ]. Therapeutic interventions targeting membrane-bound tau-containing oligomers or mTCOs, including homo tau and hetero tau–amylin aggregates at the early stage of AD, could offer new possibilities [ 36 ].…”