Cryo-EM Structures of Amyloid-β 42 Filaments from Human Brain

Key results

1. 01

   ShownType I filaments, the majority form in sporadic Alzheimer's disease, contain two identical S-shaped protofilaments that wrap each other with extended N-terminal arms across a largely hydrophobic interface. A putative bound metal ion sits next to the E22 and D23 carboxylates.

   Atomic model built in a 2.5 Å map from sporadic Alzheimer's case 1 (Krios G4 dataset); ordered core G9-A42 with S-shaped domain residues 19 to 42 and N-terminal arm 9 to 18; pseudo-21 symmetry; interface from L34, V36, V39, I41 and Y10, V12, Q15, L17; minority Type Ib (paired Type I filaments, 3.5 Å map) in sporadic cases 1 and 3. · Type I Aβ42 Filaments from Human Brain; Helical reconstruction; Model building and refinement

2. 02

   ShownType II filaments share the S-shaped fold over residues F20-A42 but differ by two flipped peptide groups. They pack with C2 symmetry through a smaller interface on the opposite face and leave hydrophobic patches exposed on the filament surface.

   Built in a 2.8 Å map from the pathological aging (PA) case; ordered core V12-A42; G25-S26 and V36-G37 peptides flipped by approximately 180°, the latter shifting the C-terminal segment by about one peptide along the helical axis; interface held by reciprocal K28 amino to A42 carboxyl salt bridges; putative metal density at E22/D23 retained. · Type II Aβ42 Filaments from Human Brain; Model building and refinement

3. 03

   SuggestedFilament type tracked disease category. A Type I majority occurred only in sporadic Alzheimer's cases, which had the most plaque cores. Type II dominated familial Alzheimer's and non-Alzheimer conditions rich in diffuse Aβ deposits, and some brains held both types.

   Ten individuals: three sporadic and two familial (APP V717F, PSEN1 F105L) Alzheimer's cases plus one case each of age-related tau astrogliopathy, Parkinson's disease dementia, dementia with Lewy bodies, GRN-mutant frontotemporal dementia and PA; Type II was 17% in sporadic case 3, Type I 24% in familial case 2; Type I cases older at death; no APOE genotype correlation. · Main Text; Type II Aβ42 Filaments from Human Brain; Discussion; Clinical history and neuropathology

4. 04

   ShownNeither in vitro assembled Aβ42 nor meningeal Aβ40 aggregates reproduce the brain folds. In vitro Aβ42 structures share an S-shaped domain but differ in side-chain contacts and protofilament packing, and NMR models of Osaka-mutant Aβ40 most resemble Type I.

   Brain Type I/II filaments are left-handed, unlike right-handed C-shaped meningeal Aβ40; seeded Aβ40 (PDB 6W0O) shares a near-identical G25-G37 conformation; none of the in vitro Aβ42 cryo-EM/NMR structures (PDB 5OQV, 2NAO, 2MXU, 5KK3) matched at residue level; Aβ40ΔE22 (Osaka) NMR models closest to Type I. · Comparison with Known Structures; Figure legends

5. 05

   ShownAβ42 filaments from homozygous App^NL-F knock-in mice were identical to human Type II. This makes the line the first experimental system reported to reproduce a brain-derived Aβ42 filament structure, which the authors link to a raised Aβ42 to Aβ40 ratio.

   Filaments extracted from brains of 18-month-old homozygous mice (C57BL/6 background; three brains pooled) carrying humanized Aβ with Swedish KM670/671NL and Iberian I716F App mutations; cryo-EM structure matched human Type II; authors note I716F, like human APP V717F, increases the Aβ42 to Aβ40 ratio. · Type II Aβ42 Filaments from AppNL-F Mouse Brain; Discussion; Mice