Small molecule-mediated therapeutic approaches to target Tau and Alzheimer's disease

Neurodegeneration is marked by the altered proteostasis and protein degradation mechanism. This is caused due to the accumulation of aberrant proteins. Alzheimer's disease is one of the leading causes of neurodegeneration characterized by the aggregation of Tau and Amyloid-β proteins intracellularly and extracellularly, respectively. The intracellular aggregation of Tau triggers accumulation of oxidative stress, loss of ER and mitochondrial function, leading to the aggravation of aggregates formation. Thus, increasing the load of aberrant proteins on chaperones and degradative mechanism, such as autophagy and ubiquitin-proteasome system. Although several small molecules are known to target and prevent Tau aggregation, the detrimental effects in the cell due to aggregates accumulation shall not be overlooked. In such instance, small molecules that effectively target Tau aggregates and the cellular aberrations would be of great importance. Here we have discussed the efficacy of natural molecule, Limonoid, isolated from Azadirachta indica that prevents Tau aggregation and also activates the heat shock protein system. The activated heat shock protein system elevates the levels of Hsp70 that is known to interact with aberrantly folded Tau. Further, the role of Hsp70 in directing Tau clearance by macroautophagy or chaperone-mediated autophagy elucidates the effect of limonoids in overcoming AD pathology due to Tau aggregation.