Role of TREM2 in Alzheimer's Disease: A Long Road Ahead.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by an increasing deterioration of memory, which is concomitant with additional cognitive deficits. Neurofibrillary tangles and senile plaques are two pivotal proteins inside the brain that are considered essential to obstruct the normal cognitive function of the brain. Genetic variations in TREM2 gene disturb the neuroinflammatory action of microglia in reducing the progression of the disease.TREM2 is a transmembrane receptor present on the microglia, which has an important function in neuroinflammation. Genome-wide association studies identified variants of TREM2 gene and linked it with the risk of developing AD, by 2-4 folds. Numerous studies on mice models have revealed the relationship between mutations of TREM2 gene and its effect on amyloid burden and tau pathology in the brain that gets affected by AD. This review summarizes the role of TREM2 and its variants in the progression of AD and tries to delve deep into the role of soluble TREM2 as an effective biomarker and impending neuroprotection in AD. It also focuses on the strategies to develop therapeutic agents against TREM2 by employing its expression, function, and signalling pathways. The current challenges posed against prospective therapy for AD are also discussed.

Gelatin grafted poly(D,L-lactide) as an inhibitor of protein aggregation: An in vitro case study.

Amyloids are a group of proteins that are capable of forming aggregated amyloid fibrils, which is responsible for many neurodegenerative diseases including Alzheimer's disease (AD). In our previous study, synthesis and characterization of star-shaped poly(D,L-lactide)-b-gelatin (ss-pLG) have been reported. In the present work, we have extended our work to study ss-pLG against protein aggregation. To the best of our knowledge, this is the first report on the inhibition of amyloid fibrillation by protein grafted poly(D,L-lactide). Bovine serum albumin (BSA) was chosen as the model protein, which readily forms fibril under high temperature. We found that ss-pLG efficiently suppressed the fibril formation of BSA compared with gelatin (Gel), which was supported by Thioflavin T assay, circular dichroism (CD) spectroscopy and atomic force microscopy (AFM). In addition, ss-pLG significantly curtailed amyloid-induced hemolysis. We also found that incubation of ss-pLG with neuroblastoma cells (MC65) protected the cells from fibril-induced toxicity. The rescuing efficiency of ss-pLG was better than Gel, which could be attributed to the reduced lamella thickness in branched ss-pLG. These results suggest the significance of gelatin grafting, which probably allows gelatin to interact with the key residues of the amyloidogenic core of BSA effectively.

Phenothiazine: A Better Scaffold against Tuberculosis.

The incidence of Tuberculosis (TB) is baffling in developing countries due to the increase in multidrug-resistant and extensively drug-resistant TB. Therefore, drugs acting through different mechanisms are in dire need to counter the resistant strains. Various chemical scaffolds are being investigated against tuberculosis, among them the molecules containing phenothiazine nucleus are found to be more effective against both susceptible and resistant strains of M. tuberculosis. In addition, the efficacy of first-line drugs has been found to be enhanced on supplementary treatment with phenothiazines. The present review provides an overview of the phenothiazine based molecules which were investigated during the last ten years for their anti-tubercular activity.

Type-II NADH Dehydrogenase (NDH-2): a promising therapeutic target for antitubercular and antibacterial drug discovery.

INTRODUCTION: Tuberculosis (TB) is highly dangerous due to the development of resistance to first-line drugs. Moreover, Mycobacterium tuberculosis (Mtb) has also developed resistance to newly approved antitubercular drug bedaquiline. This necessitates the search for drugs acting on newer molecular targets. The energy metabolism of mycobacteria is the prime focus for the discovery of novel antitubercular drugs. Targeting type-2 NADH dehydrogenase (NDH-2) involved in the production of respiratory ATP could, therefore, be effective in treating the disease. Areas covered: This review describes the energetics of mycobacteria and the role of NDH-2 in ATP synthesis. Special attention has been given for genetic and chemical validations of NDH-2 as a molecular target. The reported kinetics and crystal structures of NDH-2 have been given in detail for better understanding of the enzyme. Expert opinion: NDH-2 is an essential enzyme for ATP synthesis and has a potential role in dormancy and persistence of Mtb. The human counterpart lacks this enzyme and hence NDH-2 inhibitors could have more clinical importance. Phenothiazines are potent inhibitor of NDH-2 and are effective against both drug-susceptible and drug-resistant Mtb. Thus, it is highly desirable to optimize phenothiazine class of compounds for the development of next generation anti-TB drugs.