Natural Products for the Therapy of Proteinopathies Underlying the Neurodegenerative Conditions: Protein Misfolding and Fibrillization in Alzheimer’s Disease and Parkinson’s Disease| Biomed Grid

Significant progress has been made in our understanding of dysregulated proteostasis and protein misfolding which underlie the pathogenesis of such neurodegenerative diseases as Alzheimer's disease (AD) and Parkinson's disease (PD). In the 1990s the kinetics of β-amyloid (Aβ) fibrillization was well characterized [1,2]. Epidemiology had shown that mutations in amyloid precursor protein (APP) or the beta- and gamma-secretases which elevate the level of Aβ in the brain, as well as mutations which increase the propensity for Aβ to polymerize, are strongly associated with the development of Alzheimer's disease. Oligomers of Aβ are more neurotoxic than the monomers [3-5]. These observations suggested that molecules which would interfere with polymerization and fibrillization might slow the progression of AD. During the testing of natural compounds, Thioflavin-T (Th-T) was often used to monitor the state of Aβ polymerization [6]. The tendency for many proteins and peptides to convert from their native functional state into intractable amyloid aggregates was found to underlie multiple human disorders including Alzheimer and Parkinson diseases, type II diabetes, prion disease and several systemic amyloidosis (e.g. Aβ, αs, PrP, τ, IAPP, TDP-43, p53) [7-15]. Multiple therapeutic strategies have been employed to find disease-modifying agents against amyloidosis [16]. Some natural compounds found in the diet have anti-amyloid effects and may reduce the risk for AD and T2D [17,18]. Epidemiologic studies have suggested that diets with a high intake of flavonoids and polyphenolic compounds may have protective effects against AD, T2D and dementia [19-21]. Several polyphenols have progressed to clinical trials for the treatment of AD including resveratrol, curcumin, epigallocatechin-3-gallate (EGCG) and palm fruit bioactive [19,22,23].