Inhibition of the Self-Assembly of Aβ and of Tau by Polyphenols: Mechanistic Studies

Abstract

The amyloid-β (Aβ) peptide and tau protein are thought to play key neuropathogenic roles in Alzheimer's disease (AD). Both Aβ and tau self-assemble to form the two major pathological hallmarks of AD: amyloid plaques and neurofibrillary tangles, respectively. In this review, we show that naturally occurring polyphenols abundant in fruits, vegetables, red wine, and tea possess the ability to target pathways associated with the formation of assemblies of Aβ and tau. Polyphenols modulate the enzymatic processing of the amyloid-β precursor protein and inhibit toxic Aβ oligomerization by enhancing the clearance of Aβ42 monomer, modulating monomer-monomer interactions and remodeling oligomers to non-toxic forms. Additionally, polyphenols modulate tau hyperphosphorylation and inhibit tau β-sheet formation. The anti-Aβ-self-assembly and anti-tau-self-assembly effects of polyphenols increase their potential as preventive or therapeutic agents against AD, a complex disease that involves many pathological mechanisms.

Keywords: Alzheimer′s disease; amyloid assemblies; amyloid-β self-assembly; neurofibrillary tangles; polyphenols; tau hyperphosphorylation; tau self-assembly.

Figure 1

Isomers of resveratrol. Trans-resveratrol is more stable than cis-resveratrol and accounts for the beneficial effects of the polyphenol.

Figure 2

Under common experimental conditions, epigallocatechin-3-gallate (EGCG) forms gallocatechin-3-gallate (GCG) through epimerization, and theasinensin A and P2 through oxidation-induced dimerization.

Figure 3

Enzymatic processing of amyloid-β precursor protein (AβPP). (a) Cleavage within the amyloid-β (Aβ) sequence (i.e., at the peptide bond between Lys16 and Leu17) by α-secretase precludes Aβ production while sequential cleavages first by β-secretase, and then by γ-secretase at the sites indicated produce Aβ40 and Aβ42. (b) Amyloidogenic and non-amyloidogenic pathways and their products. Curcumin modulates the amyloidogenic pathway by inhibiting β-secretase. EGCG and curcumin facilitate the non-amyloidogenic pathway by enhancing the activity of α-secretase.

Figure 4

Modulation of the formation of toxic Aβ oligomers by polyphenols. Resveratrol enhances the clearance of Aβ monomer. Rosmarinic acid and curcumin directly inhibit oligomerization by interfering with peptide–peptide interactions while resveratrol and EGCG remodel toxic Aβ oligomers to nontoxic assemblies.

Figure 5

Rosmarinic acid undergoes conformational change from extended to bent conformation in binding to the hydrophobic pocket in insulin dimer. The formation of an aromatic cluster between bent rosmarinic acid and aromatic residues on the surface stabilizes the dimer, precluding amyloid formation.

Figure 6

Tau isoforms in the human brain. Tau consists of a projection domain and a microtubule-assembly domain. The six tau isoforms (2N4R, 1N4R, 0N4R, 2N3R, 1N3R, AND 0N3R) are designated by the number of N inserts in the former and by the number of repeats R in the latter. Calculated pI’s indicate that the isoforms except 2N3R are basic proteins. The number of potential phosphorylation sites in each isoform is indicated.

Figure 7

Polyphenols modulate levels of hyperphosphorylated tau by inhibiting GSK-3β activity towards tau, remodeling tau to kinase-resistant tau (tau*), increasing the activity of PP2A towards hyperphosphorylated tau, and enhancing the clearance of hyperphosphorylated tau.

Figure 8

Tau constructs that form filaments. K18 and K19 correspond to the repeat domains of 2N4R and 0N3R, respectively. The relative locations of the hexapeptide motifs (PHF6* (VQIINK) and PHF6 (VQIVYK)), which are thought to act as nucleating segments for tau self-assembly are indicated.

Figure 9

Polyphenols inhibit the self-assembly of full-length tau and fragments.