Beyond Amyloid: A Machine Learning-Driven Approach Reveals Properties of Potent GSK-3ß Inhibitors Targeting Neurofibrillary Tangles.

Current treatments for Alzheimer's disease (AD) focus on slowing memory and cognitive decline, but none offer curative outcomes. This study aims to explore and curate the common properties of active, drug-like molecules that modulate glycogen synthase kinase 3ß (GSK-3ß), a well-documented kinase with increased activity in tau hyperphosphorylation and neurofibrillary tangles-hallmarks of AD pathology. Leveraging quantitative structure-activity relationship (QSAR) data from the PubChem and ChEMBL databases, we employed seven machine learning models: logistic regression (LogR), k-nearest neighbors (KNN), random forest (RF), support vector machine (SVM), extreme gradient boosting (XGB), neural networks (NNs), and ensemble majority voting. Our goal was to correctly predict active and inactive compounds that inhibit GSK-3ß activity and identify their key properties. Among the six individual models, the NN demonstrated the highest performance with a 79% AUC-ROC on unbalanced external validation data, while the SVM model was superior in accurately classifying the compounds. The SVM and RF models surpassed NN in terms of Kappa values, and the ensemble majority voting model demonstrated slightly better accuracy to the NN on the external validation data. Feature importance analysis revealed that hydrogen bonds, phenol groups, and specific electronic characteristics are important features of molecular descriptors that positively correlate with active GSK-3ß inhibition. Conversely, structural features like imidazole rings, sulfides, and methoxy groups showed a negative correlation. Our study highlights the significance of structural, electronic, and physicochemical descriptors in screening active candidates against GSK-3ß. These predictive features could prove useful in therapeutic strategies to understand the important properties of GSK-3ß candidate inhibitors that may potentially benefit non-amyloid-based AD treatments targeting neurofibrillary tangles.

The Inhibition Effect of Epigallocatechin-3-Gallate on the Co-Aggregation of Amyloid-ß and Human Islet Amyloid Polypeptide Revealed by Replica Exchange Molecular Dynamics Simulations.

Alzheimer's disease and Type 2 diabetes are two epidemiologically linked diseases which are closely associated with the misfolding and aggregation of amyloid proteins amyloid-ß (Aß) and human islet amyloid polypeptide (hIAPP), respectively. The co-aggregation of the two amyloid proteins is regarded as the fundamental molecular mechanism underlying their pathological association. The green tea extract epigallocatechin-3-gallate (EGCG) has been extensively demonstrated to inhibit the amyloid aggregation of Aß and hIAPP proteins. However, its potential role in amyloid co-aggregation has not been thoroughly investigated. In this study, we employed the enhanced-sampling replica exchange molecular dynamics simulation (REMD) method to investigate the effect of EGCG on the co-aggregation of Aß and hIAPP. We found that EGCG molecules substantially diminish the ß-sheet structures within the amyloid core regions of Aß and hIAPP in their co-aggregates. Through hydrogen-bond, π-π and cation-π interactions targeting polar and aromatic residues of Aß and hIAPP, EGCG effectively attenuates both inter-chain and intra-chain interactions within the co-aggregates. All these findings indicated that EGCG can effectively inhibit the co-aggregation of Aß and hIAPP. Our study expands the potential applications of EGCG as an anti-amyloidosis agent and provides therapeutic options for the pathological association of amyloid misfolding disorders.

Re-Engineering Therapeutic Anti-Aß Monoclonal Antibody to Target Amyloid Light Chain.

Amyloidosis involves the deposition of misfolded proteins. Even though it is caused by different pathogenic mechanisms, in aggregate, it shares similar features. Here, we tested and confirmed a hypothesis that an amyloid antibody can be engineered by a few mutations to target a different species. Amyloid light chain (AL) and ß-amyloid peptide (Aß) are two therapeutic targets that are implicated in amyloid light chain amyloidosis and Alzheimer's disease, respectively. Though crenezumab, an anti-Aß antibody, is currently unsuccessful, we chose it as a model to computationally design and prepare crenezumab variants, aiming to discover a novel antibody with high affinity to AL fibrils and to establish a technology platform for repurposing amyloid monoclonal antibodies. We successfully re-engineered crenezumab to bind both Aß42 oligomers and AL fibrils with high binding affinities. It is capable of reversing Aß42-oligomers-induced cytotoxicity, decreasing the formation of AL fibrils, and alleviating AL-fibrils-induced cytotoxicity in vitro. Our research demonstrated that an amyloid antibody could be engineered by a few mutations to bind new amyloid sequences, providing an efficient way to reposition a therapeutic antibody to target different amyloid diseases.

Sensory gamma entrainment: Impact on amyloid protein and therapeutic mechanism.

The deposition of amyloid ß peptide (Aß) is one of the main pathological features of AD. The much-talked sensory gamma entrainment may be a new treatment for Aß load. Here we reviewed the generation and clearance pathways of Aß, aberrant gamma oscillation in AD, and the therapeutic effect of sensory gamma entrainment on AD. In addition, we discuss these results based on stimulus parameters and possible potential mechanisms. This provides the support for sensory gamma entrainment targeting Aß to improve AD.

Inhibition of primary and secondary nucleation alongwith disruption of amyloid fibrils and alleviation of associated cytotoxicity: A biophysical insight of a novel property of Chlorpropamide (an anti-diabetic drug).

Aggregation of physiologically synthesized soluble proteins to insoluble, cytotoxic fibrils is a pre-requisite for pathogenesis of amyloid associated disorders including Alzheimer's disease, non-systemic amyloidosis, Parkinson's disease, etc. Considerable advancement has been made to understand the mechanism behind aggregation process but till date we have no efficient cure and preventive therapy for associated diseases. Strategies to prevent protein aggregation are nevertheless many which have been proved promisingly successful in vitro. One of those is repurposing already approved drugs that saves time and money too and has been employed in this study. Here, for the first time we are reporting the effectiveness of an anti-diabetic drug chlorpropamide (CHL) under dosage conditions, a novel property to inhibit aggregation in human lysozyme (HL) in vitro. Spectroscopic (Turbidity, RLS, ThT, DLS, ANS) and microscopic (CLSM) results demonstrates that CHL has the potency to suppress aggregation in HL up to 70 %. CHL is shown to affect the elongation of fibrils with IC50 value of 88.5 µM as clear from the kinetics results, may be by interacting near/with aggregation prone regions of HL. Hemolytic assay also revealed the reduced cytotoxicity in the presence of CHL. Disruption of amyloid fibrils and inhibition of secondary nucleation in the presence of CHL was also evidenced by ThT, CD and CLSM results with reduced cytotoxicity as confirmed by hemolytic assay. We also performed preliminary studies on α-synuclein fibrillation inhibition and surprisingly found that CHL is not just inhibiting the fibrillation but also stabilizing the protein in its native state. These findings insinuate that CHL (anti-diabetic) possess multiple roles and can be a promising drug for developing therapeutic against non-systemic amyloidosis, Parkinson's disease and other amyloid associated disorders.

Current study on diagnosis and treatment of Alzheimer's disease by targeting amyloid b-protein.

Alzheimer's disease (AD), also known as senile dementia, is a degenerative disease of the central nervous system and is characterized by insidious onset and a chronic progressive course. It is the most common type of senile dementia. Studies have proved that the deposition of amyloid b (Ab) in the brain is one of the initiating factors correlated to the pathology of AD, and it acts as one of the critical factors leading to the onset of AD. A large number of long-term studies have shown that Ab may be a therapeutic target for a breakthrough in the treatment of AD. This review elucidates the important role of Ab in the development of AD, current research on the role of Ab in AD pathogenesis, and treatment of AD by targeting Ab.

Antimicrobial and Amyloidogenic Activity of Peptides. Can Antimicrobial Peptides Be Used against SARS-CoV-2?

At present, much attention is paid to the use of antimicrobial peptides (AMPs) of natural and artificial origin to combat pathogens. AMPs have several points that determine their biological activity. We analyzed the structural properties of AMPs, as well as described their mechanism of action and impact on pathogenic bacteria and viruses. Recently published data on the development of new AMP drugs based on a combination of molecular design and genetic engineering approaches are presented. In this article, we have focused on information on the amyloidogenic properties of AMP. This review examines AMP development strategies from the perspective of the current high prevalence of antibiotic-resistant bacteria, and the potential prospects and challenges of using AMPs against infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).