A pinboard by
Narendran Annadurai

PhD student, Institute of Molecular and Translational Medicine, Palacky University, Olomouc


Focused on therapeutic strategy for Alzheimer's disease

Alzheimer's disease (AD) is one of the leading cause of death in developed countries characterized by plaques and tangles in the brain causes cognitive decline in elderly population. This is the only disease which has no early diagnosis and treatment. My focus is on the protein aggregates called tau tangles and its phosphorylating kinases. When this tau protein is hyperphosphorylated it will aggregate and causes microtubule disruption results in the loss of nutrient, signal transport between neurons causes neuronal loss. These tau aggregates then causes neurodegeneration and impairment cognitive function of the brain. Elderly people affected with dementia (loss of memory) will not be able to identify their family, relatives and even themselves at severe stages of the disease. Around 45 million people living with Alzheimer's disease worldwide makes Alzheimer's research community to find the new treatment strategies. So finding inhibitors against the kinases that are responsible for the tau aggregation is an important strategy. My another topic is focused on inhibiting the aggregation process with small molecule compounds which can cross blood-brain barrier for effective treatment. I am also focused on using compounds to clear the pre-formed tau aggregates.This strategy will be really effective for the treatment of Alzheimer's disease as the disease causes mental and financial burdens in people's lives.


Inhibition of Tau protein aggregation by rhodanine-based compounds solubilized via specific formulation additives to improve bioavailability and cell viability.

Abstract: Anti-aggregation drugs play an important role in therapeutic approaches for Alzheimer's disease. We have previously developed a number of compounds that are able to inhibit the pathological aggregation of Tau protein. One common obstacle to application is the limited penetration across the plasma membranes into cells, where Tau aggregation occurs in the cytosol. We used an inducible N2a cell line which expresses the repeat domain of tau and develops tau aggregates.Several peptide-polymer conjugates were synthesized to enhance the uptake of compounds into cells and thus to improve their biomedical application. The aim of this study was to test whether the peptide-inhibitor complexes still retain their inhibitory activity on Tau aggregation.We screened peptide sequences with high binding capacity to a subset of aggregation inhibitors and identified them by fluorescence microscopy and MALDI MS/MS with regard to drug solubilization. To explore whether the synthesized complexes can influence the aggregation propensity of Tau we performed in vitro and cellular assays. The effect on toxicity was investigated by measuring apoptosis markers.The tested peptide-compound complexes show no decrease in the total Tau levels but decreased ratios of soluble to pelletable Tau species. This indicates a conversion of insoluble Tau oligomers into soluble forms which appear to be less toxic than the insoluble ones, as seen by a decrease of apoptotic cells. Thus the peptide-compound complexes have a higher potency than the compounds alone due to improved bioavailability of the drug.

Pub.: 06 Feb '17, Pinned: 27 Jun '17