Hollow core of Alzheimer’s A β ₄₂ amyloid observed by cryoEM is relevant at physiological pH

Abstract

Recent cryoEM density maps of A β 42 fibrils obtained at low pH revealed two protofilaments winding around a hollow core raising the question if such tubular structures also exist at physiological pH. Based on the cryoEM measurements and on NMR data, we probe amyloid fibril organizations corresponding to the observed cryoEM density map. Our study demonstrates that the tubular A β 42 fibril models exist at both acidic and physiological pH; however, the relative populations of the polymorphic models shift with pH. At acidic pH, the hollow core model exhibits higher population than the other models; at physiological pH, although it is less populated compared to the other models, structurally, it is stable and represents 8% of the population. We observe that only models with C termini facing the external surface of the fibril retain the hollow core under acidic and physiological conditions with dimensions similar to those observed by cryoEM; on the other hand, the hydrophobic effect shrinks the tubular cavity in the alternative organization. The existence of the hollow core fibril at physiological pH emphasizes the need to examine toxic effects of minor oligomeric species with unique organizations.

Polymorphic Triple β-Sheet Structures Contribute to Amide Hydrogen/Deuterium (H/D) Exchange Protection in the Alzheimer Amyloid β42 Peptide

“…These experimental observations and the triple ␤-sheet fibril model highlight recent findings of the N-terminal role in the formation of the tubular A␤ fibril (32,45). The coexistence of globulomer and fibril also suggests that there are critical intermediates (8,34) that could lead to both ADDL-like (Amyloid ␤-Derived Diffusible Ligands) and fibril amyloids.…”

“…Based on experimental and computational work, we consider a possible turn around Gly 9 -His 14 (13,32). We tested triple ␤-sheet protofilament conformations, in which the N-terminal region of A␤42 folds back to a conventional double ␤-sheet core (Fig.…”

Pulsed hydrogen–deuterium exchange mass spectrometry probes conformational changes in amyloid beta (Aβ) peptide aggregation

“…By using this method, we successfully decoupled the aggregation from the HDX process. Importantly, we extracted kinetic information on the Aβ 42 aggregation at 25°C, indicating that the middle region of the Aβ 42 peptide (i.e., [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] was the "seeding" region in aggregation, followed by the C-terminus hydrophobic region (i.e., [36][37][38][39][40][41][42] and then the N-terminus hydrophilic region (i.e., [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Finally, we showed that this approach allowed us to examine directly the factors that affect the oligomerization of Aβ 42 .…”

“…Studies of amyloid fibrils invoke X-ray crystallography (22-24), EM (19,25,26), and thioflavin T fluorescence (19, 27), revealing the polypeptide's global behavior, whereas NMR studies provide residue-level information for the fibrils (28-30). Nevertheless, we know little about soluble Aβ aggregates owing to their intrinsically high heterogeneity.…”

Coexistence of ribbon and helical fibrils originating from hIAPP 20–29 revealed by quantitative nanomechanical atomic force microscopy

“…Hollow fibril structures have recently been reported for Alzheimer's Aβ 40 or Aβ 42 using electron microscopy and solidstate NMR spectroscopy (27,46,47). In these fibrils, the fulllength peptides fold as hairpins and align with the long axis to form a β sheet, where the hydrophobic effect drives the formation of the hollow core.…”