Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids

  • Alzheimer, A. Über eine eigenartige Erkrankung der Hirnrinde. Allg. Z. Psychiatr. 64, 146–148 (1907).

    Google Scholar 

  • Fischer, O. Miliare Nekrosen mit drusigen Wucherungen der Neurofibrillen, eine regelmässige Veränderung der Hirnrinde bei seniler Demenz. Monatsschr. Psychiatr. Neurol. 22, 361–372 (1907).

    Google Scholar 

  • Lewy, F. H. in Handbuch der Neurologie (ed. Lewandowsky, M.) 920–933 (Springer Verlag, 1912).

  • Divry, P. & Florkin, M. Sur les propriétés optiques de l’amyloïde. C. R. Soc. Biol. 97, 1808–1810 (1927).

    Google Scholar 

  • Ladewig, P. Double-refringence of the amyloid–Congo-red-complex in histological sections. Nature 156, 81–82 (1945).

    ADS 

    Google Scholar 

  • Cohen, A. S. & Calkins, E. Electron microscopic observations on a fibrous component in amyloid of diverse origins. Nature 183, 1202–1203 (1959).

    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Glenner, G. G. & Wong, C. W. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120, 885–890 (1984).

    CAS 
    PubMed 

    Google Scholar 

  • Masters, C. L. et al. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl Acad. Sci. USA 82, 4245–4249 (1985).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Brion, J., Passareiro, H., Nunez, J. & Flament-Durand, J. Mise en évidence immunologique de la protéine tau au niveau des lésions de dégénérescence neurofibrillaire de la maladie d’Alzheimer. Arch. Biol. 95, 229–235 (1985).

    Google Scholar 

  • Goedert, M., Wischik, C. M., Crowther, R. A., Walker, J. E. & Klug, A. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc. Natl Acad. Sci. USA 85, 4051–4055 (1988).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Spillantini, M. G. et al. α-Synuclein in Lewy bodies. Nature 388, 839–840 (1997).

    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006).

    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Arai, T. et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem. Biophys. Res. Commun. 351, 602–611 (2006).

    CAS 
    PubMed 

    Google Scholar 

  • Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349, 704–706 (1991).

    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Poorkaj, P. et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann. Neurol. 43, 815–825 (1998).

    CAS 
    PubMed 

    Google Scholar 

  • Hutton, M. et al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702–705 (1998).

    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Spillantini, M. G. et al. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl Acad. Sci. USA 95, 7737–7741 (1998).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Polymeropoulos, M. H. et al. Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science 276, 2045–2047 (1997).

    CAS 
    PubMed 

    Google Scholar 

  • Kabashi, E. et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat. Genet. 40, 572–574 (2008).

    CAS 
    PubMed 

    Google Scholar 

  • Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668–1672 (2008).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Eanes, E. D. & Glenner, G. G. X-ray diffraction studies on amyloid filaments. J. Histochem. Cytochem. 16, 673–677 (1968).

    CAS 
    PubMed 

    Google Scholar 

  • Sunde, M. et al. Common core structure of amyloid fibrils by synchrotron X-ray diffraction. J. Mol. Biol. 273, 729–739 (1997).

    CAS 
    PubMed 

    Google Scholar 

  • Kidd, M. Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature 197, 192–193 (1963).

    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Crowther, R. A. Straight and paired helical filaments in Alzheimer disease have a common structural unit. Proc. Natl Acad. Sci. USA 88, 2288–2292 (1991).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Nelson, R. et al. Structure of the cross-β spine of amyloid-like fibrils. Nature 435, 773–778 (2005).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Rodriguez, J. A. et al. Structure of the toxic core of α-synuclein from invisible crystals. Nature 525, 486–490 (2015).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lu, J.-X. et al. Molecular structure of β-amyloid fibrils in Alzheimer’s disease brain tissue. Cell 154, 1257–1268 (2013).

    CAS 
    PubMed 

    Google Scholar 

  • Petkova, A. T. et al. A structural model for Alzheimer’s β-amyloid fibrils based on experimental constraints from solid state NMR. Proc. Natl Acad. Sci. USA 99, 16742–16747 (2002).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tuttle, M. D. et al. Solid-state NMR structure of a pathogenic fibril of full-length human α-synuclein. Nat. Struct. Mol. Biol. 23, 409–415 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sachse, C., Fändrich, M. & Grigorieff, N. Paired β-sheet structure of an Aβ(1–40) amyloid fibril revealed by electron microscopy. Proc. Natl Acad. Sci. USA 105, 7462–7466 (2008).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhang, R. et al. Interprotofilament interactions between Alzheimer’s Aβ1–42 peptides in amyloid fibrils revealed by cryoEM. Proc. Natl Acad. Sci. USA 106, 4653–4658 (2009).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kühlbrandt, W. The resolution revolution. Science 343, 1443–1444 (2014).

    ADS 
    PubMed 

    Google Scholar 

  • He, S. & Scheres, S. H. W. Helical reconstruction in RELION. J. Struct. Biol. 198, 163–176 (2017). This paper reports the development of new image-processing algorithms that enabled cryo-EM structure determination of amyloid filaments to sufficient resolution for de novo atomic modelling.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Fitzpatrick, A. W. P. et al. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547, 185–190 (2017). The is the first report of cryo-EM structures of amyloid filaments purified from human brain—tau filaments from Alzheimer’s disease.

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Weingarten, M. D., Lockwood, A. H., Hwo, S. Y. & Kirschner, M. W. A protein factor essential for microtubule assembly. Proc. Natl Acad. Sci. USA 72, 1858–1862 (1975).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Peng, C., Trojanowski, J. Q. & Lee, V. M.-Y. Protein transmission in neurodegenerative disease. Nat. Rev. Neurol. 16, 199–212 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wischik, C. M. et al. Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc. Natl Acad. Sci. USA 85, 4884–4888 (1988).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Falcon, B. et al. Tau filaments from multiple cases of sporadic and inherited Alzheimer’s disease adopt a common fold. Acta Neuropathol. 136, 699–708 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Falcon, B. et al. Structures of filaments from Pick’s disease reveal a novel tau protein fold. Nature 561, 137–140 (2018).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Falcon, B. et al. Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature 568, 420–423 (2019).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhang, W. et al. Novel tau filament fold in corticobasal degeneration. Nature 580, 283–287 (2020).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Arakhamia, T. et al. Posttranslational modifications mediate the structural diversity of tauopathy strains. Cell 180, 633–644.e12 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Shi, Y. et al. Structure-based classification of tauopathies. Nature 598, 359–363 (2021). This article classifies tauopathies on the basis of the atomic structures of tau filaments.

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hallinan, G. I. et al. Structure of tau filaments in prion protein amyloidoses. Acta Neuropathol. 142, 227–241 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Qi, C. et al. Tau filaments from amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) adopt the CTE fold. Preprint at bioRxiv (2023).

  • Qi, C. et al. Identical tau filaments in subacute sclerosing panencephalitis and chronic traumatic encephalopathy. Acta Neuropathol. Commun. 11, 74 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wesseling, H. et al. Tau PTM profiles identify patient heterogeneity and stages of Alzheimer’s disease. Cell 183, 1699–1713.e13 (2020).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Maroteaux, L., Campanelli, J. T. & Scheller, R. H. Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J. Neurosci. 8, 2804–2815 (1988).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Davidson, W. S., Jonas, A., Clayton, D. F. & George, J. M. Stabilization of α-synuclein secondary structure upon binding to synthetic membranes. J. Biol. Chem. 273, 9443–9449 (1998).

    CAS 
    PubMed 

    Google Scholar 

  • Schweighauser, M. et al. Structures of α-synuclein filaments from multiple system atrophy. Nature 585, 464–469 (2020). This study describes the first structures of α-synuclein filaments from human brains.

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yang, Y. et al. Structures of α-synuclein filaments from human brains with Lewy pathology. Nature 610, 791–795 (2022).

    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Yang, Y. et al. New SNCA mutation and structures of α-synuclein filaments from juvenile-onset synucleinopathy. Acta Neuropathol. 145, 561–572 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tziortzouda, P., Van Den Bosch, L. & Hirth, F. Triad of TDP-43 control in neurodegeneration: autoregulation, localization and aggregation. Nat. Rev. Neurosci. 22, 197–208 (2021).

    CAS 
    PubMed 

    Google Scholar 

  • Mackenzie, I. R. A. et al. A harmonized classification system for FTLD–TDP pathology. Acta Neuropathol. 122, 111–113 (2011).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Arseni, D. et al. Structure of pathological TDP-43 filaments from ALS with FTLD. Nature 601, 139–143 (2022). This study describes the first structures of TDP-43 filaments from human brains.

    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Arseni, D. et al. TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP. Nature 620, 898–903 (2023).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tsuji, H. et al. Molecular analysis and biochemical classification of TDP-43 proteinopathy. Brain 135, 3380–3391 (2012).

    PubMed 

    Google Scholar 

  • Haass, C. et al. Amyloid β-peptide is produced by cultured cells during normal metabolism. Nature 359, 322–325 (1992).

    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Shoji, M. et al. Production of the Alzheimer amyloid β protein by normal proteolytic processing. Science 258, 126–129 (1992).

    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Kang, J. et al. The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733–736 (1987).

    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Tcw, J. & Goate, A. M. Genetics of β-amyloid precursor protein in Alzheimer’s disease. Cold Spring Harb. Perspect. Med. 7, a024539 (2017).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Nilsberth, C. et al. The ‘Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced Aβ protofibril formation. Nat. Neurosci. 4, 887–893 (2001).

    CAS 
    PubMed 

    Google Scholar 

  • Kollmer, M. et al. Cryo-EM structure and polymorphism of Aβ amyloid fibrils purified from Alzheimer’s brain tissue. Nat. Commun. 10, 4760 (2019). This study reports the first structures of amyloid-β filaments from human brain blood vessels.

    ADS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yang, Y. et al. Cryo-EM structures of amyloid-β 42 filaments from human brains. Science 375, 167–172 (2022). This study reports the first structures of amyloid-β filaments from human brain parenchyma.

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yang, Y. et al. Cryo-EM structures of amyloid-β filaments with the Arctic mutation (E22G) from human and mouse brains. Acta Neuropathol. 145, 325–333 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Schöll, M. et al. Low PiB PET retention in presence of pathologic CSF biomarkers in Arctic APP mutation carriers. Neurology 79, 229–236 (2012).

    PubMed 

    Google Scholar 

  • Schweighauser, M. et al. Age-dependent formation of TMEM106B amyloid filaments in human brains. Nature 605, 310–314 (2022).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Jiang, Y. X. et al. Amyloid fibrils in FTLD-TDP are composed of TMEM106B and not TDP-43. Nature 605, 304–309 (2022).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chang, A. et al. Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases. Cell 185, 1346–1355.e15 (2022). References 67–69 report the discovery of previously unknown TMEM106B amyloid filaments using cryo-EM.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Perneel, J. et al. Accumulation of TMEM106B C-terminal fragments in neurodegenerative disease and aging. Acta Neuropathol. 145, 285–302 (2023).

    CAS 
    PubMed 

    Google Scholar 

  • Vicente, C. T. et al. C-terminal TMEM106B fragments in human brain correlate with disease-associated TMEM106B haplotypes. Brain (2023).

  • Van Deerlin, V. M. et al. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat. Genet. 42, 234–239 (2010).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Klunk, W. E. et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh compound-B. Ann. Neurol. 55, 306–319 (2004).

    CAS 
    PubMed 

    Google Scholar 

  • Xia, C.-F. et al. [18F]T807, a novel tau positron emission tomography imaging agent for Alzheimer’s disease. Alzheimers Dement. 9, 666–676 (2013).

    PubMed 

    Google Scholar 

  • van Dyck, C. H. et al. Lecanemab in early Alzheimer’s disease. N. Engl. J. Med. 388, 9–21 (2023). This report describes a trial of the first mechanism-based therapy for Alzheimer’s disease with a measurable improvement in cognitive decline.

    PubMed 

    Google Scholar 

  • Zhou, Y., Li, J., Nordberg, A. & Ågren, H. Dissecting the binding profile of PET tracers to corticobasal degeneration tau fibrils. ACS Chem. Neurosci. 12, 3487–3496 (2021).

    CAS 
    PubMed 

    Google Scholar 

  • Künze, G. et al. Molecular simulations reveal distinct energetic and kinetic binding properties of [18F]PI-2620 on tau filaments from 3R/4R and 4R tauopathies. ACS Chem. Neurosci. 13, 2222–2234 (2022).

    PubMed 

    Google Scholar 

  • Shi, Y. et al. Cryo-EM structures of tau filaments from Alzheimer’s disease with PET ligand APN-1607. Acta Neuropathol. 141, 697–708 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Merz, G. E. et al. Stacked binding of a small molecule PET tracer to Alzheimer’s tau paired helical filaments. Preprint at bioRxiv (2022).

  • Shi, Y., Ghetti, B., Goedert, M. & Scheres, S. H. W. Cryo-EM structures of chronic traumatic encephalopathy tau filaments with PET ligand flortaucipir. J. Mol. Biol. 435, 168025 (2023).

    CAS 

    Google Scholar 

  • Pagnon de la Vega, M. et al. The Uppsala APP deletion causes early onset autosomal dominant Alzheimer’s disease by altering APP processing and increasing amyloid β fibril formation. Sci. Transl. Med. 13, eabc6184 (2021).

    CAS 
    PubMed 

    Google Scholar 

  • Gremer, L. et al. Fibril structure of amyloid-β(1–42) by cryo-electron microscopy. Science 358, 116–119 (2017).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Liu, D. et al. O-Glycosylation induces amyloid-β to form new fibril polymorphs vulnerable for degradation. J. Am. Chem. Soc. 143, 20216–20223 (2021).

    CAS 
    PubMed 

    Google Scholar 

  • Zhang, W. et al. Heparin-induced tau filaments are polymorphic and differ from those in Alzheimer’s and Pick’s diseases. eLife 8, e43584 (2019).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Abskharon, R. et al. Cryo-EM structure of RNA-induced tau fibrils reveals a small C-terminal core that may nucleate fibril formation. Proc. Natl Acad. Sci. USA 119, e2119952119 (2022).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Frieg, B. et al. The 3D structure of lipidic fibrils of α-synuclein. Nat. Commun. 13, 6810 (2022).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Li, B. et al. Cryo-EM of full-length α-synuclein reveals fibril polymorphs with a common structural kernel. Nat. Commun. 9, 3609 (2018).

    ADS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Li, Y. et al. Amyloid fibril structure of α-synuclein determined by cryo-electron microscopy. Cell Res. 28, 897–903 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Guerrero-Ferreira, R. et al. Cryo-EM structure of α-synuclein fibrils. eLife 7, e36402 (2018).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Ni, X., McGlinchey, R. P., Jiang, J. & Lee, J. C. Structural insights into α-synuclein fibril polymorphism: effects of Parkinson’s disease-related C-terminal truncations. J. Mol. Biol. 431, 3913–3919 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Guerrero-Ferreira, R. et al. Two new polymorphic structures of human full-length α-synuclein fibrils solved by cryo-electron microscopy. eLife 8, e48907 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Boyer, D. R. et al. Structures of fibrils formed by α-synuclein hereditary disease mutant H50Q reveal new polymorphs. Nat. Struct. Mol. Biol. 26, 1044–1052 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhao, K. et al. Parkinson’s disease-related phosphorylation at Tyr39 rearranges α-synuclein amyloid fibril structure revealed by cryo-EM. Proc. Natl Acad. Sci. USA 117, 20305–20315 (2020).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhao, K. et al. Parkinson’s disease associated mutation E46K of α-synuclein triggers the formation of a distinct fibril structure. Nat. Commun. 11, 2643 (2020).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sun, Y. et al. Cryo-EM structure of full-length α-synuclein amyloid fibril with Parkinson’s disease familial A53T mutation. Cell Res. 30, 360–362 (2020).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Boyer, D. R. et al. The α-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure. Proc. Natl Acad. Sci. USA 117, 3592–3602 (2020).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Long, H. et al. Wild-type α-synuclein inherits the structure and exacerbated neuropathology of E46K mutant fibril strain by cross-seeding. Proc. Natl Acad. Sci. USA 118, e2012435118 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sun, Y. et al. The hereditary mutation G51D unlocks a distinct fibril strain transmissible to wild-type α-synuclein. Nat. Commun. 12, 6252 (2021).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cao, Q., Boyer, D. R., Sawaya, M. R., Ge, P. & Eisenberg, D. S. Cryo-EM structures of four polymorphic TDP-43 amyloid cores. Nat. Struct. Mol. Biol. 26, 619–627 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Li, Q., Babinchak, W. M. & Surewicz, W. K. Cryo-EM structure of amyloid fibrils formed by the entire low complexity domain of TDP-43. Nat. Commun. 12, 1620 (2021).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kumar, S. T. et al. Seeding the aggregation of TDP-43 requires post-fibrillization proteolytic cleavage. Nat. Neurosci. 26, 983–996 (2023).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Stern A. M, et al.Abundant Aβ fibrils in ultracentrifugal supernatants of aqueous extracts from Alzheimer’s disease brains. Neuron 111, 2012–2020.e4 (2023).

    PubMed 

    Google Scholar 

  • Riek, R. & Eisenberg, D. S. The activities of amyloids from a structural perspective. Nature 539, 227–235 (2016).

    ADS 
    PubMed 

    Google Scholar 

  • Lövestam, S. et al. Assembly of recombinant tau into filaments identical to those of Alzheimer’s disease and chronic traumatic encephalopathy. eLife 11, e76494 (2022). This article describes an in vitro assembly reaction with recombinant protein that replicates the structures of filaments extracted from human brains.

    PubMed 
    PubMed Central 

    Google Scholar 

  • Wischik, C. M. et al. Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc. Natl Acad. Sci. USA 85, 4506–4510 (1988).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Al-Hilaly, Y. K. et al. Tau (297–391) forms filaments that structurally mimic the core of paired helical filaments in Alzheimer’s disease brain. FEBS Lett. 594, 944–950 (2020).

    CAS 
    PubMed 

    Google Scholar 

  • Goedert, M., Spillantini, M. G., Cairns, N. J. & Crowther, R. A. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8, 159–168 (1992).

    CAS 
    PubMed 

    Google Scholar 

  • Lövestam, S. & Scheres, S. H. W. High-throughput cryo-EM structure determination of amyloids. Faraday Discuss. 240, 243–260 (2022).

    ADS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).

    CAS 
    PubMed 

    Google Scholar 

  • Braak, H. et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging 24, 197–211 (2003).

    PubMed 

    Google Scholar 

  • Brettschneider, J. et al. Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann. Neurol. 74, 20–38 (2013).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Irwin, D. J. et al. Deep clinical and neuropathological phenotyping of Pick disease. Ann. Neurol. 79, 272–287 (2016).

    CAS 
    PubMed 

    Google Scholar 

  • Duyckaerts, C., Uchihara, T., Seilhean, D., He, Y. & Hauw, J. J. Dissociation of Alzheimer type pathology in a disconnected piece of cortex. Acta Neuropathol. 93, 501–507 (1997).

    CAS 
    PubMed 

    Google Scholar 

  • Frost, B. & Diamond, M. I. Prion-like mechanisms in neurodegenerative diseases. Nat. Rev. Neurosci. 11, 155–159 (2010).

    CAS 
    PubMed 

    Google Scholar 

  • Jucker, M. & Walker, L. C. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45–51 (2013).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Prusiner, S. B. Prions. Proc. Natl Acad. Sci. USA 95, 13363–13383 (1998).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Holec, S. A. M. & Woerman, A. L. Evidence of distinct α-synuclein strains underlying disease heterogeneity. Acta Neuropathol. 142, 73–86 (2021).

    CAS 
    PubMed 

    Google Scholar 

  • Jarrett, J. T. & Lansbury, P. T. Seeding ‘one-dimensional crystallization’ of amyloid: a pathogenic mechanism in Alzheimer’s disease and scrapie? Cell 73, 1055–1058 (1993).

    CAS 
    PubMed 

    Google Scholar 

  • Sanders, D. W. et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82, 1271–1288 (2014).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Meyer-Luehmann, M. et al. Exogenous induction of cerebral β-amyloidogenesis is governed by agent and host. Science 313, 1781–1784 (2006).

    ADS 
    CAS 
    PubMed 

    Google Scholar 

  • Clavaguera, F. et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat. Cell Biol. 11, 909–913 (2009).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mougenot, A.-L. et al. Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol. Aging 33, 2225–2228 (2012).

    CAS 
    PubMed 

    Google Scholar 

  • Luk, K. C. et al. Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. J. Exp. Med. 209, 975–986 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Porta, S. et al. Patient-derived frontotemporal lobar degeneration brain extracts induce formation and spreading of TDP-43 pathology in vivo. Nat. Commun. 9, 4220 (2018).

    ADS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Burger, D., Fenyi, A., Bousset, L., Stahlberg, H. & Melki, R. Cryo-EM structure of α-synuclein fibrils amplified by PMCA from PD and MSA patient brains. Preprint at bioRxiv (2021).

  • Fan, Y. et al. Conformational change of α-synuclein fibrils in cerebrospinal fluid from different clinical phases of Parkinson’s disease. Structure 31, 78–87.e5 (2023).

    CAS 
    PubMed 

    Google Scholar 

  • Ghosh, U., Thurber, K. R., Yau, W.-M. & Tycko, R. Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer’s disease brain tissue. Proc. Natl Acad. Sci. USA 118, e2023089118 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Xiao, Y. et al. Aβ(1–42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer’s disease. Nat. Struct. Mol. Biol. 22, 499–505 (2015).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Qiang, W., Yau, W.-M., Lu, J.-X., Collinge, J. & Tycko, R. Structural variation in amyloid-β fibrils from Alzheimer’s disease clinical subtypes. Nature 541, 217–221 (2017).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lövestam, S. et al. Seeded assembly in vitro does not replicate the structures of α-synuclein filaments from multiple system atrophy. FEBS Open Bio 11, 999–1013 (2021).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Tarutani, A. Cryo-EM structures of tau filaments from SH-SY5Y cells seeded with brain extracts from cases of Alzheimer’s disease and corticobasal degeneration. FEBS Open Bio 13, 1394–1404 (2023).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Shahnawaz, M. et al. Discriminating α-synuclein strains in Parkinson’s disease and multiple system atrophy. Nature 578, 273–277 (2020).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Siderowf, A. et al. Assessment of heterogeneity among participants in the Parkinson’s Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study. Lancet Neurol. 22, 407–417 (2023).

    CAS 
    PubMed 

    Google Scholar 

  • Cohen, S. I. A. et al. Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism. Proc. Natl Acad. Sci. USA 110, 9758–9763 (2013).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Benilova, I., Karran, E. & De Strooper, B. The toxic Aβ oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat. Neurosci. 15, 349–357 (2012).

    CAS 
    PubMed 

    Google Scholar 

  • Cremades, N. et al. Direct observation of the interconversion of normal and toxic forms of α-synuclein. Cell 149, 1048–1059 (2012).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Weismiller, H. A. et al. Structural disorder in four-repeat Tau fibrils reveals a new mechanism for barriers to cross-seeding of Tau isoforms. J. Biol. Chem. 293, 17336–17348 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Jackson, S. J. et al. Short fibrils constitute the major species of seed-competent tau in the brains of mice transgenic for human P301S tau. J. Neurosci. 36, 762–772 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Legname, G. et al. Continuum of prion protein structures enciphers a multitude of prion isolate-specified phenotypes. Proc. Natl Acad. Sci. USA 103, 19105–19110 (2006).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Morozova, O. A., March, Z. M., Robinson, A. S. & Colby, D. W. Conformational features of tau fibrils from Alzheimer’s disease brain are faithfully propagated by unmodified recombinant protein. Biochemistry 52, 6960–6967 (2013).

    CAS 
    PubMed 

    Google Scholar 

  • Falcon, B. et al. Conformation determines the seeding potencies of native and recombinant tau aggregates. J. Biol. Chem. 290, 1049–1065 (2015).

    CAS 
    PubMed 

    Google Scholar 

  • Saito, T. et al. Single App knock-in mouse models of Alzheimer’s disease. Nat. Neurosci. 17, 661–663 (2014).

    CAS 
    PubMed 

    Google Scholar 

  • Leistner, C. et al. The in-tissue molecular architecture of β-amyloid in the mammalian brain. Nat. Commun. 14, 2833 (2022).

    ADS 

    Google Scholar 

  • Zielinski, M. et al. Cryo-EM structures of amyloid-β fibrils from Alzheimer’s disease mouse models. Preprint at bioRxiv (2023).

  • Hallinan, G. I. et al. Cryo-EM structures of prion protein filaments from Gerstmann–Sträussler–Scheinker disease. Acta Neuropathol. 144, 509–520 (2022). This study reports first structures of prion protein filaments from human brains.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Murray, K. A. et al. De novo designed protein inhibitors of amyloid aggregation and seeding. Proc. Natl Acad. Sci. USA 119, e2206240119 (2022).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sahtoe, D. D. et al. Design of amyloidogenic peptide traps. Preprint at bioRxiv (2023).

  • Seidler, P. M. et al. Structure-based discovery of small molecules that disaggregate Alzheimer’s disease tissue derived tau fibrils in vitro. Nat. Commun. 13, 5451 (2022).

    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Englund, H. et al. Sensitive ELISA detection of amyloid-β protofibrils in biological samples. J. Neurochem. 103, 334–345 (2007).

    CAS 
    PubMed 

    Google Scholar 

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