Abstract
Aggregation of amyloid β42 (Aβ42) is one of the hallmarks of Alzheimer’s disease (AD). There are numerous naturally occurring products that suppress the aggregation of Aβ42, but the underlying mechanisms remain to be elucidated. Based on NMR and MS spectroscopic analysis, we propose three structural characteristics found in natural products required for the suppressive activity against Aβ42 aggregation (i.e., oligomerization by targeting specific amino acid residues on this protein). These characteristics include (1) catechol-type flavonoids that can form Michael adducts with the side chains of Lys16 and 28 in monomeric Aβ42 through flavonoid autoxidation; (2) non-catechol-type flavonoids with planarity due to α,β-unsaturated carbonyl groups that can interact with the intermolecular β-sheet region in Aβ42 aggregates, especially aromatic rings such as those of Phe19 and 20; and (3) carboxy acid derivatives with triterpenoid or anthraquinoid that can generate a salt bridge with basic amino acid residues such as Lys16 and 28 in the Aβ42 dimer or trimer. Here, we summarize the recent body of knowledge concerning amyloidogenic inhibitors, particularly in functional food components and Kampo medicine, and discuss their application in the treatment and prevention of AD.
Highlights
Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder
The two pathological hallmarks of AD are the accumulation of amyloid β (Aβ) protein deposits in extracellular senile plaques and the accumulation of tau protein induced from hyperphosphorylation mainly by glycogen synthase kinase 3 β (GSK-3β) in intracellular neurofibrillary tangles [1]
Aβ itself is considered a physiological by-product of cellular metabolism because it can be detected as a circulating protein in the cerebrospinal fluid and blood of healthy humans [3]; the physiological function of Aβ is summarized in a recent review by Panza et al [4]
Summary
Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder. The two pathological hallmarks of AD are the accumulation of amyloid β (Aβ) protein deposits in extracellular senile plaques and the accumulation of tau protein induced from hyperphosphorylation mainly by glycogen synthase kinase 3 β (GSK-3β) in intracellular neurofibrillary tangles [1]. The amyloid cascade hypothesis, originally proposed by Hardy and Higgins [2], is widely accepted. This hypothesis holds that the deposition of Aβ is the earliest event in AD progression, and that Aβ aggregation can trigger the tau-related pathologies of AD. The ability of Aβ42 to aggregate (i.e., oligomerize and fibrillize), and to show neurotoxicity, is higher than that of Aβ40. Because there remain unanswered questions regarding which types of oligomers contribute the most to the pathogenesis of AD, developing multi-target inhibitors for these higher-order oligomers is imperative for making meaningful progress toward AD therapy. The mechanisms underlying the anti-aggregative activity of most of these natural products remain to be elucidated. We discuss the in vivo metabolism of these inhibitors, including blood–brain barrier permeability and brain–gut interaction, toward developing anti-AD drugs
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