Tea polyphenols as multi-target therapeutics for Alzheimer's disease: An in silico study

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease characterized by cognitive decline, dementia, and in later stages complete loss of feelings, sensation and death. The global prevalence of the disease is on the rise, and it affects 35-40% of the population above 80 years. The pathological hallmarks of the disease include extra-neuronal deposition of amyloid-β (Aβ) as plaques and intra-neuronal hyperphosphorylated tau protein as neurofibrillary tangles, which cause neurodegeneration and cerebral atrophy. Aβ deposition is catalyzed by β-secretase and γ-secretase, while tau hyperphosphorylation is catalyzed by glycogen synthase kinase - 3β (GSK-3β). With neurodegeneration, the level of the neurotransmitter acetylcholine (ACh), as well as acetylcholinesterase (AChE), decreases in the synaptic cleft, called cholinergic deficiency. This leads to the cardinal behavioural abnormalities of AD, which is referred to as cholinergic hypothesis of AD. The other enzyme which degrades ACh is the butyrylcholinesterase (BuChE). Thus, current treatment options of AD include symptomatic treatment to elevate the levels of ACh by inhibiting AChE. However, the currently used drugs cause several side effects, and the quest for novel drugs remains an interesting and essential venture. Since the disease has multiple pathophysiologies, there is an unrelenting need to develop novel drugs and lead molecules capable of inhibiting multiple pathways. The present study hypothesizes use of tea polyphenols against the key drug targets of AD, viz. β-Secretase, γ-Secretase, GSK-3β, AChE and BuChE. The hypothesis has been validated using molecular docking tools. The result indicates that the polyphenols may potentially inhibit these enzymes, similar to their known inhibitors. Thus, the findings are of immense significance in the therapeutic interventions of AD, using tea polyphenols as exciting multi-target drugs.