Phytocompounds as modulators of HSF1 in neurodegenerative disease: Special emphasis on Alzheimer's disease.

Alzheimer's disease (AD) is the most common age-related neurodegenerative disease that affects millions of people every year globally. In addition to a drastic rise in AD cases, there is a significant increase in the death rate as well. According to the latest statistics, the death rate increased to 1.62 million in 2019 and is expected to rise further. The primary pathological hallmark of the disease is the accumulation of misfolded aggregates, such as amyloid beta (Aβ) plaques and tau neurofibrillary tangles, which induce toxic effects and initiate neuronal dysfunction, ultimately leading to disease symptoms, including cognitive impairment. Hence, targeting and eliminating these protein aggregates could significantly inhibit the disease pathogenesis. Previous studies have also suggested that the activation of heat shock factor 1 (HSF1) and the up-regulation of its encoded heat shock proteins (HSPs) can clear toxic aggregates by triggering proteostasis mechanisms, such as autophagy and the ubiquitin-proteasome system (UPS). However, in neurodegenerative diseases (NDs) like AD, the proteotoxic stress response (PSR) is defective and can't effectively remove harmful aggregates. In such conditions, the forced activation of HSF1 and its targeted molecular chaperone proteins, such as HSPs, by using various plant-derived compounds, such as celastrol, curcumin, and resveratrol, has shown promising neuroprotective effects by eliminating protein aggregates across multiple AD models. Hence, this review focused on various plant-derived compounds and their mode of activating HSF1 and its encoded HSPs. This review also described other compounds from multiple natural sources that affect HSF1 and HSPs in different disease models. In this way, the current review will be a complete reference for natural compounds that activate HSF1 and help researchers identify potential drug candidates for NDs like Alzheimer's disease.