Biophysical and in Vivo Studies Identify a New Natural-Based Polyphenol, Counteracting Aβ Oligomerization in Vitro and Aβ Oligomer-Mediated Memory Impairment and Neuroinflammation in an Acute Mouse Model of Alzheimer’s Disease

Abstract

In this study natural-based complex polyphenols, obtained through a smart synthetic approach, have been evaluated for their ability to inhibit the formation of Aβ42 oligomers, the most toxic species causing synaptic dysfunction, neuroinflammation, and neuronal death leading to the onset and progression of Alzheimer’s disease. In vitro neurotoxicity tests on primary hippocampal neurons have been employed to select nontoxic candidates. Solution NMR and molecular docking studies have been performed to clarify the interaction mechanism of Aβ42 with the synthesized polyphenol derivatives, and highlight the sterical and chemical requirements important for their antiaggregating activity. NMR results indicated that the selected polyphenolic compounds target Aβ42 oligomeric species. Combined NMR and docking studies indicated that the Aβ42 central hydrophobic core, namely, the 17–31 region, is the main interaction site. The length of the peptidomimetic scaffold and the presence of a guaiacol moiety were identified as important requirements for the antiaggregating activity. In vivo experiments on an Aβ42 oligomer-induced acute mouse model highlighted that the most promising polyphenolic derivative (PP04) inhibits detrimental effects of Aβ42 oligomers on memory and glial cell activation. NMR kinetic studies showed that PP04 is endowed with the chemical features of true inhibitors, strongly affecting both the Aβ42 nucleation and growth rates, thus representing a promising candidate to be further developed into an effective drug against neurodegenerative diseases of the amyloid type.

Healthy Effects of Plant Polyphenols: Molecular Mechanisms

“…Biophenols can also be used to develop new drugs useful to combat chronic inflammatory conditions, the risk of thrombosis, CVD-related states such as atherosclerosis [28], cancer [29], also in combination with anti-cancer drugs [30], as well as to reduce amyloid deposition associated with T2DM and aging-related states such as neurodegeneration [1,31] ( Figure 1). Finally, the molecular scaffolds of plant polyphenols are also investigated to develop new molecules potentially exploitable in disease prevention and therapy [32]. The beneficial effects of olive and other plant polyphenols can be hindered by the reduced bioavailability of the latter following reduced intestinal absorption and their rapid biotransformation in the organism; in addition, chemical modifications of many polyphenols by gut microbiota further reduces their bioavailability and biological efficacy [33].…”

Catechins as Tools to Understand the Molecular Basis of Neurodegeneration

“…Studying the interaction of the most abundant green tea catechin, EGCG, and its analogs with Aβ toxic oligomers, is a valuable means to elucidate the molecular mechanisms underlying the toxicity of Aβ oligomers and dissect the determinants of oligomer toxicity. For example, using a library of catechins it was possible to map toxic surfaces within soluble Aβ assemblies and such surfaces are anticipated to enable the design of new anti-amyloid therapeutics [ 21 , 24 , 34 , 38 ].…”

“…In general, these studies elucidate how the most abundant catechin, EGCG, reduces the cytotoxicity of Aβ oligomers and the resulting mechanisms provide a foundation to develop EGCG-based amyloid inhibitors. As an illustrative example, in the following sections we describe the characterization of the structural determinants of catechin binding to amyloid oligomers and the development of new synthetic polyphenol-based amyloid inhibitors [ 37 , 38 ].…”

“…For example, Lambruschini et al developed a library of complex synthetic polyphenols inspired by natural catechins ( Figure 5 b) [ 37 ]. Following this initial work, Tomaselli et al investigated both in vitro and in vivo the most promising members of the library and their ability to interact and inhibit oligomeric Aβ [ 38 ]. They selected four polyphenolic compounds from the library based on their inhibitory efficacy and synthetized two additional new compounds lacking the catechin polyphenolic rings ( Figure 5 c).…”

“…Here, we focus on summarizing the use of catechins as tools for mapping the determinants of Aβ and αSyn amyloid toxicity through examples from the literature and our own work [ 21 , 27 , 34 , 35 , 36 ]. In addition, we also present other studies where the previous knowledge of catechin-based amyloid inhibition was useful for the synthesis of new phenolic compounds [ 12 , 37 , 38 ]. This manuscript does not claim to be exhaustive and for an account of other mechanistic studies on catechins and amyloids, the reader is referred to other excellent reviews in the field [ 32 , 39 , 40 , 41 , 42 , 43 , 44 ].…”