Based on molecular structures: Amyloid-β generation, clearance, toxicity and therapeutic strategies

Abstract

Amyloid-β (Aβ) has long been considered as one of the most important pathogenic factors in Alzheimer's disease (AD), but the specific pathogenic mechanism of Aβ is still not completely understood. In recent years, the development of structural biology technology has led to new understandings about Aβ molecular structures, Aβ generation and clearance from the brain and peripheral tissues, and its pathological toxicity. The purpose of the review is to discuss Aβ metabolism and toxicity, and the therapeutic strategy of AD based on the latest progress in molecular structures of Aβ. The Aβ structure at the atomic level has been analyzed, which provides a new and refined perspective to comprehend the role of Aβ in AD and to formulate therapeutic strategies of AD.

Keywords: Alzheimer’s disease; amyloid-β; molecular structure; therapeutic strategies; toxicity.

FIGURE 1

The oligomerization and fiber formation of Aβ₄₂ and Aβ₄₀: The monomers of Aβ₄₂ and Aβ₄₀ first form a dimmer, and a dimmer further forms a tetramer. The tetrameric Aβ₄₂ structure (bending structure) is can be added with Aβ₄₂ monomer or dimer to form Aβ₄₂ hexamer (sub-nucleus). The two Aβ₄₂ hexamers form a dodecamer (one stack paranuclear dimer). The natural structure of the Aβ₄₂ monomer is converted to a β-sheet structure (the rate-limiting step in which the oligomer forms fibers) occurs at the 12-mer level. The tetrameric Aβ₄₀ is in a ring structure, resisting further addition of Aβ₄₀ monomer or dimer, fibers are also formed by other means.

FIGURE 2

The secondary nucleation: Secondary nucleation includes two ways for catalyzing nucleation on the surface of Aβ fibers (top panel) and fiber breakage (bottom panel). Aβ monomer is catalyzed to form oligomers (new nuclei) on the surface of fibers. The Aβ fiber recruitment monomer is further extended by recruiting monomers and the ever-expanding fiber can be broken into two seeds (short segments) as a new aggregated nuclei.

FIGURE 3

Two molecular structures of Aβ40 fibrils [figures coming from Lu et al. (2013) and Schutz et al. (2015)]. (A) Schematic view of the lowest-energy conformer of an Aβ1-40 E22Δ bi-decamer (2 × 10 monomers). The symmetry axis (arrow) coincides with the long axis of the fibril. (B) NMR bundle of the middle layer only. (C) Cross section of the fibril hydrophobic residues is colored white, negatively charged residues red, positively charged residues blue, and polar ones (and Gly) green. (D) Structure with the lowest total experimental restraint energy in Xplor-NIH calculations. The threefold-symmetric repeat unit is shown, as viewed along the fibril growth axis. Backbone and sidechain carbon atoms are gray and green, respectively. (E) Superposition of 20 structures that are consistent with experimental restraints (PDB code 2M4J). Sidechains of the three Aβ40 molecules in the repeat unit are yellow, green, or orange. (F,G) Two views of the idealized fibril structure, created by repeating the trimeric unit 18 times with 0.48 nm displacements along the fibril axis. (H,I) Structural models for Aβ40 fibril polymorphs with threefold and twofold symmetry about the fibril growth axis, developed previously from solid-state NMR and electron microscopy measurements on fibrils grown in vitro.

FIGURE 4

Two molecular models of Aβ42 fibrils architecture and atomic model of the fibril cross section [figures coming from Eisenberg and Sawaya (2016) and Gremer et al. (2017)]. (A) The near-atomic resolution model determined by solid-state NMR by Wälti et al. Two double-horseshoe–shaped molecules of amyloid-β(1–42) are shown (black and gray) related by a twofold axis (marked by a circle), which runs down the center of the fibril. The N-terminal 14 residues are disordered; one possible conformation is shown here by dotted lines. Many of the known familial mutations are carried by residues located on the outer surface (red). The surface hydrophobic patch formed by residues V40 and A42 (orange) may explain the greater rate of secondary nucleation by the 1–42 species compared with 1–40. (B). The lower resolution (5–7 Å) model determined by Schmidt et al. by cryo-EM is another polymorph of amyloid-β(1–42), also with two molecules per layer, related by a twofold axis, and also with a poorly ordered N terminus. The gray color represents a slice through the cryo-EM map. The two molecules appear to be related by a homo-steric zipper type of bonding. In both A and B, the models are viewed down the fibril axis on the left and nearly perpendicular to the fibril axis on the right. (C) A hetero-zipper in amyloid-β(1–42) fibrils from Wälti et al. (D) A homo-zipper from GNNQQNY. (E) A noncontiguous homo-zipper from Wälti et al. Dotted lines represent intervening residues. (F) Side view of the atomic model showing the staggered arrangement of the non-planar subunits. (G) Surface representation of a fragment of the atomic fibril model. The surface is colored according to hydrophobicity (Kyte-Doolittle scale) [gradient from brown (hydrophobic, 4.5) to white (neutral, 0.0)]. View of the “ridge” (H) and “groove” (I) fibril ends. (J) Two subunits, one from each protofilament, are shown (blue and brown) together with the masked EM density map. (K) Detailed view of the interactions between the N- and C-terminus and the sidechain of Lys28 (at contour level of 1 σ). (L) Side view of the same two opposing subunits showing the relative orientation of the non-planar subunits.

FIGURE 5

Pathways of amyloid precursor protein (APP) processing and amyloid-β (Aβ) generation: ➀ APP further modifies the endoplasmic reticulum and Golgi and synthesizes it via the endoplasmic reticulum. ➁ APP transports to the cell membrane through vesicles. ➂A The α-secretase cleaves APP on the cell membrane as sAPP_α and C₈₃. ➂B The β-secretase cleaves APP into sAPP_β and C₉₉ in the endosomes. ➃ The γ-secretase complex cleaves C₉₉ into AICD and Aβ in mitochondrial membrane, multivesicular body or lysosome membrane.

FIGURE 6

Proposed toxicity mechanisms caused by Aβ oligomers: The toxicity mechanism mainly includes two aspects, one is the cell-to-cell transmission, and the other is the influence on the intracellular system. Cell-to-cell transmission includes (A) Secretory vesicle mechanism, (B) Intermembrane bridge Mechanisms and (C) The release and uptake of naked proteins. The influence on the intracellular system includes ➀ ER stress, ➁ Mitochondria disfunction, ➂ Signaling interruption, and ➃ Lysosomal leakage.

FIGURE 7

Links of Aβ metabolism in the brain, plasma and peripheral tissues and possible targets for therapy.