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Unraveling Alzheimer’s complexity with a distinct Aβ42 fibril type and specific AV-45 binding

Nature Chemical Biology (2025)Cite this article

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Abstract

Abnormal aggregation of amyloid-β protein (1–42) (Aβ42) is the primary pathology in Alzheimer’s disease (AD). Two types of Aβ42 fibrils have been identified in the insoluble fraction of diseased human brains. Here, we report that the fraction previously deemed ‘soluble’ during sarkosyl extraction of AD brains actually harbors numerous amyloid fibrils, with a looser bundling than those in the insoluble fraction. Using cryo-electron microscopy (cryo-EM), we discover a third type (type III) of Aβ42 fibril that is occasionally found in the soluble but not insoluble fraction of one AD brain. We also reveal that cryo-EM structures of Aβ42 fibrils complexed with the positron emission tomography tracer AV-45 show a ligand-binding channel within type I but not type III Aβ42 fibrils. In this binding channel, AV-45 engages with a vertical geometry. Through the discovery of this new structural polymorph of ex vivo Aβ42 fibril, our study highlights the notable structural heterogeneity of Aβ fibrils among persons with AD.

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Fig. 1: IHC of the brain slices derived from three persons with AD.
Fig. 2: Characterization of Aβ42 amyloid fibrils in the soluble fraction of AD brains.
Fig. 3: Sedimentation and clustering behaviors of fibrils extracted from the AD1 case.
Fig. 4: Cryo-EM structure of the type III Aβ42 fibril.
Fig. 5: AV-45 binds to an interior channel of the type I Aβ42 fibril.

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Data availability

The cryo-EM maps were deposited to the EM Data Bank (EMDB) under accession numbers EMD-37170 for the AD1 type I Aβ42 fibril of soluble fraction, EMD-37197 for the AD1 type III Aβ42 fibril of soluble fraction, EMD-37195 for the type I:AV-45 complex, EMD-37200 for the type III:AV-45 complex, EMD-37198 for the AD2 type I Aβ42 fibril of soluble fraction and EMD-37199 for the AD3 type I Aβ42 fibril of soluble fraction. The corresponding refined atomic models of the AD1 type I, AD3 type III Aβ42, type I:AV-45, type III:AV-45, AD2 type I and AD3 type I fibrils were deposited to the PDB under accession numbers 8KEW, 8KF3, 8KF1, 8KF6, 8KF4 and 8KF5, respectively. The density maps used are available from the EMDB under accession number EMD-33055 (type 3 TMEM106B fibril). The structural models used in this study are available from the PDB under accession codes 7Q4B (type I Aβ42 fibril) and 7Q4M (type II Aβ42 fibril).

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Acknowledgements

We thank the participants and their families for donating brain tissues. We thank X. Qian for pathological evaluation, X. Wang, W. Ju, Y. Fu and H. Xiao for brain slide preparation and staining and N. Wang, D. Zhang and Z. Chen for obtaining tissue samples. We thank staff members in the National Human Brain Bank for Development and Function, Chinese Academy of Medical Science and Peking Union Medical College for brain sample preparation. We acknowledge the Cryo-EM center at the Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry for help with data collection. We are grateful to M. Fändrich and L. Radamaker (Ulm University) for their help with the code to map the origin of the fibril segments in the cryo-EM micrographs. This work was supported by the National Natural Science Foundation of China (92353302 to D.L.; 82188101 and 22425704 to C.L.; 32170683 to D.L.), the Shanghai Basic Research Pioneer Project (to L.T. and C.L.), the Shanghai Pilot Program for Basic Research, Chinese Academy of Sciences, Shanghai Branch (CYJ-SHFY-2022-005 to C.L.), the Chinese Academy of Sciences Project for Young Scientists in Basic Research (YSBR-095 to C.L.), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB1060000 to C.L.), the Chinese Academy of Medical Science Innovation Fund for Medical Sciences (2021-I2M-1-025 to W.Q.) and the STI2030-Major Project (2021ZD0201100, task 1 2021ZD0201101 to W.Q.; 2021ZD0201100, task 1 2021ZD0201101 to C.M. and W.Q.). Dr. Cong Liu is a SANS Exploration Scholar.

Author information

Author notes

  1. These authors contributed equally: Qinyue Zhao, Youqi Tao.

Authors and Affiliations

  1. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China

    Qinyue Zhao, Youqi Tao, Yuxuan Yao, Bingyao Cui, Tianyi Cao & Dan Li

  2. Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai, China

    Qinyue Zhao, Youqi Tao, Yuxuan Yao, Bingyao Cui, Tianyi Cao & Dan Li

  3. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

    Kaien Liu, Shiran Lv & Cong Liu

  4. State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Kaien Liu, Shiran Lv & Cong Liu

  5. Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, China

    Weidi Xiao & Chu Wang

  6. Center for Brain Health and Brain Technology, Global Institute of Future Technology, Shanghai Jiao Tong University, Shanghai, China

    Weidong Li

  7. Department of Neurology, Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

    Feng Gao & Yong Shen

  8. Neurodegenerative Disorder Research Center, Anhui Province Key Laboratory of Biomedical Aging Research, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

    Feng Gao & Yong Shen

  9. Department of Human Anatomy, Histology and Embryology, Institute of Basic Medical Sciences, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China

    Chao Ma & Wenying Qiu

  10. Shanghai Academy of Natural Sciences (SANS), Fudan University, Shanghai, China

    Cong Liu

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  1. Qinyue Zhao
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Contributions

Q.Z., C.L. and D.L. designed the project. W.Q., C.M., W.L., F.G. and Y.S. supplied human brain tissue. Q.Z. performed the IHC staining. S.L. and Y.Y. assisted with the staining process. Q.Z. and Y.T. prepared the cryo-EM samples and performed the cryo-EM data collection and processing. K.L., Y.Y., B.C. and T.C. helped with the cryo-EM data processing. W.X., Q.Z., Y.T. and C.W. performed the MS sample preparation, data acquisition and data processing. All authors were involved in analyzing the data and contributed to paper discussion and editing. Q.Z., Y.T., C.L. and D.L. wrote the paper.

Corresponding authors

Correspondence to Wenying Qiu, Cong Liu or Dan Li.

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Nature Chemical Biology thanks Stefano Ricagno and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Sarkosyl-based extraction of amyloid fibrils from the brains of three AD patients.

Workflow of the extraction procedure and NS-TEM images of samples are shown. The solid arrows depict the steps with fibrils obtained: blue arrows highlight the purification steps for the sarkosyl-insoluble fraction (P2); red arrows highlight the purification steps for the sarkosyl-soluble fraction (S2). The grey dash arrows depict the steps with no fibril observed. Samples framed with dotted lines were used for further cryo- EM reconstruction.

Extended Data Fig. 2 Evaluation of the resolution of cryo-EM maps and refined models.

Fourier shell correlation (FSC) curves for cryo-EM maps and corresponding structures of fibrils in (a) soluble, (b) insoluble fraction of AD1; (c) AV45 bound Aβ Type I and Type III fibrils in AD1; Type I in soluble fraction from (d) AD2 and (e) AD3 patients. The overall resolution was estimated based on gold-standard 0.143 Fourier shell correlation (FSC) of two independently refined cryo-EM half maps, which are shown in black; for the final refined atomic model against final cryo-EM map shown in red; for the refined atomic model against the two half maps depicted in orange and blue dotted lines, respectively. The local resolution plots of the recombinant 3D density maps are estimated by the ‘Local resolution’ program in RELION 4.0.

Extended Data Fig. 3 Cryo-EM structures of the Type I Aβ42 fibrils in the soluble fraction of the AD brains.

a. Density map of the Type I Aβ42 fibril in the soluble fraction of the AD1 brain. The two protofilaments were colored in purple and pink, respectively. The map shows one crossover (360° helical turn) of the fibril. Zoomed-in side view and cross- section view are shown below. The fibrill width and helical parameters of the fibril are indicated. Extra densities are colored in orange. b-d. Structural models of Type I Aβ42 fibrils obtained from AD1 (b), AD2 (c) and AD3 (d) are fitted in their density maps. The density maps are restricted to areas within 2 Å radius of the structural models. Extra densities are colored in orange. e. Structure comparison of the Type I Aβ42 fibrils obtained from the soluble fraction of the brains of AD1-3 cases (this work) and that obtained from the insoluble fraction of AD brains (PDB ID: 7Q4B). r.m.s.d. for AD1 (pink) versus AD2 (blue): 0.191 over 63 Cα atoms; AD1 versus AD3 (orange): 0.145 over 61 Cα atoms; AD1 versus 7Q4B (gray): 0.398 over 67 Cα atoms (global alignments).

Extended Data Fig. 4 Histograms of the distribution of crossover points per unit length for each type of fibrils.

For each fibril type, n = 80 fibrils. The fitted Gaussians lines are colored in consistent with Fig. 3.

Extended Data Fig. 5 Handedness characterization for Type III Aβ42 fibril.

a. Atomic force microscopic (AFM) image (left) of the Type III Aβ42 fibril. Analysis of the periodic spacing along the fibril, indicated with a white line and arrowheads on the image, is shown on the right. Graphic illustration of fibril chirality is shown. b. Cryo-EM density of central β-strand segments of the Type III Aβ42 fibril with structural model fitted in. The density map was determined with left-handed (left) and right-handed (right) helical parameters, respectively. Correspondingly, a refined left-handed or right-handed structural model was fitted in. The backbone carbonyls fit the density better in the left-handed model as validated by the post real-space refinement statistics indicated on the top. CC, correlation coefficient between the masked map and the model; Rama., favored Ramachandran orientations; Rota., favored rotamer orientations.

Extended Data Fig. 6 Type III Aβ42 fibril forms two distinct folds.

a The models of three protofilaments Type III Aβ42 fibril can be divided into two folds, fold 1’ (composing Chain A and Chain B) and fold 2 (Chain C). Three protofilaments are aligned separately in the same ‘S-shape’ orientation, shown in sticks and cartoon loop, and then colored in purple (Chain A), cyan (Chain B) and green (Chain C), respectively. b Structure comparison of two protofilaments, Chain A (purple) and Chain B (cyan) structures in Type III Aβ42 fibril. The structural models are shown in sticks, with all the residues labeled. Global alignments (9-42) indicated the r.m.s.d of Type III Chain A versus Chain B is 0.485 Å over 32 Cα atoms. c Type III chain C and Type II Aβ42 protofilament previous reported (PDB: 7Q4B) are overlaid and colored in green and grey, respectively. The r.m.s.d between two protofilaments is 0.339 over 30 Cα atoms (global alignments).

Extended Data Fig. 7 Comparison of extra densities in the Aβ42 fibrils.

Structures of the Type I (a) and the Type III (b) fibrils extracted from the soluble fraction of AD1, and the Type II fibril (PDB:7Q4B) (c) are shown. One layer of Aβ42 structure in each fibril is shown. Residues composing the protofilamental interface are shown in spheres in the left panels. Extra densities are shown in orange and zoomed in on the right, where residues surround the extra densities are labeled and highlighted in spheres.

Extended Data Fig. 8 Cryo-EM analysis for ex vivo fibrils extracted from AD1 by using water-based extraction method.

a Workflow of the water-based fibril extraction procedure. Solid arrows depict the steps used in the next step. P5 was used for cryo-EM analysis. b NS-TEM images of the supernatants of the 12-time repeat wash highlighted in (a). Samples 9–12 framed with a red frame were combined as S4. c Representative cryo-EM micrograph of P5 from one of 16,305 movies. d The 3 most populated 2D class averages of fibrils in P5. Fibril polymorph was determined based on the crossover distance (pitch), fibril width and morphology. Type I fibrils are labeled in green; Type III fibrils are labeled in orange. Constructed using 2× binned particles of the full set of segments after the removal of picking artifacts. The box size is ∼87 nm.

Extended Data Fig. 9 Structural characterization and comparison of ex vivo Aβ42 fibrils after incubating with AV-45.

a., b. Representative cryo-EM micrographs of AD1 soluble Type I (a) and Type III (b) fibrils incubated with AV-45. Insets: 2D class averages. c Cross-section of density maps from previously reported ex vivo Aβ42 fibrils extracted from the brains of sporadic AD patients by sarkosyl-based extraction method (top, EMD-ID: EMD-13800) and water-based soaking method (bottom, EMD- ID: EMD-15770). Potential solvent densities in the AV-45 binding channel are indicated in red arrow heads. d Structural comparison between the soluble Type I fibrils of AD1 with and without the addition of AV-45. One half of structural model is shown in sticks, and the other half is shown by main chains. R.m.s.d. between these two structures is 0.305 over 64 Cα atoms (global alignments).e., f. Cross-section view of the Type III:AV-45 complex density map (e) and the structural model fitted in the density map within 2-Å radius of the model (f). Extra densities are colored in orange. g. Structural comparison between the Type III fibrils of AD1 with and without the addition of AV-45. The r.m.s.d. between the two structures is 0.527 over 80 Cα atoms (global alignments).

Extended Data Fig. 10 Structural comparison of tg-APPArcSwe fibril and AD Type I and III Aβ42 fibrils.

a., b. Structural models of Type III Aβ42 (a) and tg-APPArcSwe (b) fibrils fitted in their density maps. The density map is restricted to areas within 2-Å radius of the structural model. The protofilamental interfaces enclosing extra densities were shaded in green and zoomed in. Extra densities of cofactors are colored in orange. c. Structural comparison of the Type III Aβ42 fibrils and tg-APPArcSwe Aβ fibril (PDB ID: 8OL7). R.m.s.d.= 1.17 Å over 23 Cα atoms. Segment F20-A30 is framed with dotted box and zoomed in below with E22G mutation in mouse Aβ labeled. d Structural comparison of the Type I Aβ42 fibrils and tg-APPArcSwe Aβ fibril. R.m.s.d.= 0.145 over 61 Cα atoms.

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Supplementary Figs. 1–7, Tables 1–4 and References.

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Zhao, Q., Tao, Y., Yao, Y. et al. Unraveling Alzheimer’s complexity with a distinct Aβ42 fibril type and specific AV-45 binding. Nat Chem Biol (2025). https://doi.org/10.1038/s41589-025-01921-4

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