Amyloid β-Protein Assembly and Alzheimer Disease (2008)

The biochemistry of amyloid proteins has been a fascinating and important area of research because of its contribution to our understanding of protein folding dynamics and assembly and of the pathogenetic mechanisms of human disease. One such disease is AD, 2The abbreviations used are: AD, Alzheimer disease; Aβ, amyloid β-protein; Met35(O), Met35 sulfoxide; AFM, atomic force microscopy; CAA, cerebral amyloid angiopathy; ADDLs, Aβ-derived diffusible ligands.2The abbreviations used are: AD, Alzheimer disease; Aβ, amyloid β-protein; Met35(O), Met35 sulfoxide; AFM, atomic force microscopy; CAA, cerebral amyloid angiopathy; ADDLs, Aβ-derived diffusible ligands. the most common neurodegenerative disorder of aging. In AD, Aβ (Fig. 1A), which is expressed normally and ubiquitously throughout life as a 40–42-residue peptide, forms fibrils that deposit in the brain as "amyloid plaques." This pathologic deposition process led researchers to investigate fibril formation as a target for therapeutic intervention. In doing so, an increasing number of fibril precursors and nonfibrillar Aβ assemblies have been identified, the majority of which are neurotoxic. These findings have altered prevailing fibril-centered views of the pathobiology of amyloid diseases (1Kirkitadze M.D. Bitan G. Teplow D.B. J. Neurosci. Res. 2002; 69: 567-577Crossref PubMed Scopus (503) Google Scholar) and intensified efforts to understand the early folding and assembly dynamics of Aβ. In the discussion that follows, we seek to introduce the reader to the complex world of Aβ assembly and biological activity, a goal we hope will provide a conceptual framework upon which further knowledge or experimentation may be built.Aβ Fibril StructureThe determination of the structure of fibrils has been an unusually difficult problem because Aβ belongs to a class of proteins that are "natively unfolded" (2Nelson R. Eisenberg D. Curr. Opin. Struct. Biol. 2006; 16: 260-265Crossref PubMed Scopus (322) Google Scholar) and preferentially form amyloid fibrils rather than protein crystals. This has precluded x-ray diffraction studies of full-length Aβ and made solution NMR studies problematic (3Teplow D.B. Methods Enzymol. 2006; 413: 20-33Crossref PubMed Scopus (169) Google Scholar). Nevertheless, site-directed spin labeling and solid-state NMR studies have been informative. The former studies have revealed that Aβ fibrils comprise β-strands organized in a parallel, in-register fashion. The latter studies showed that in Aβ40 fibrils, residues 12–24 and 30–40 form parallel β-sheets and that these two β-strand segments are connected by a turn involving residues 25–29 (4Tycko R. Methods Enzymol. 2006; 413: 103-122Crossref PubMed Scopus (47) Google Scholar). Hydrogen/deuterium exchange coupled with solution-state NMR revealed a similar, but distinct, segmental arrangement of β-strands within Aβ42 fibrils. Here, residues 18–26 and 31–42 form the β-strands. In both models, salt bridges between Asp23 and Lys28 stabilize the turn region connecting the two β-strands (2Nelson R. Eisenberg D. Curr. Opin. Struct. Biol. 2006; 16: 260-265Crossref PubMed Scopus (322) Google Scholar, 5Finder V.H. Glockshuber R. Neurodegener. Dis. 2007; 4: 13-27Crossref PubMed Scopus (253) Google Scholar). Similar findings have been obtained using other methods (5Finder V.H. Glockshuber R. Neurodegener. Dis. 2007; 4: 13-27Crossref PubMed Scopus (253) Google Scholar, 6Fändrich M. CMLS Cell. Mol. Life Sci. 2007; 64: 2066-2078Crossref PubMed Scopus (198) Google Scholar).Differences among the studies likely result from the examination of different peptides (Aβ40 versus Aβ42), the absence or presence of Met35(O), or the conditions under which fibrils were formed. All these factors have been shown to affect significantly peptide assembly and biological activity (6Fändrich M. CMLS Cell. Mol. Life Sci. 2007; 64: 2066-2078Crossref PubMed Scopus (198) Google Scholar, 7Kodali R. Wetzel R. Curr. Opin. Struct. Biol. 2007; 17: 48-57Crossref PubMed Scopus (319) Google Scholar). Although no crystal structures have been determined with full-length Aβ, exciting work has been done on microcrystals formed by C-terminal peptides. These microcrystals yield diffraction patterns consistent with an in-register cross-β-organization of two interdigitated β-sheets. This "steric zipper" structure has been found in at least 13 other amyloid protein microcrystals (8Sawaya M.R. Sambashivan S. Nelson R. Ivanova M.I. Sievers S.A. Apostol M.I. Thompson M.J. Balbirnie M. Wiltzius J.J.W. McFarlane H.T. Madsen A. Riekel C. Eisenberg D. Nature. 2007; 447: 453-457Crossref PubMed Scopus (1783) Google Scholar). Whether steric zippers exists in Aβ fibrils is unclear.Pathways of Peptide AssemblyHow do monomers form fibrils? This question is fundamental to understanding fibrillogenesis and for identifying assembly steps that could be therapeutic targets. Influential early investigations promulgated the idea that Aβ assembly was a specific example of the general class of nucleation-dependent polymerization reactions (Fig. 1B). These reactions comprise a slow nucleation step, producing a "lag phase" during assembly monitoring, followed by a rapid fibril elongation step. Operating within this paradigm, nucleation (kn) and elongation (ke) rate constants for Aβ fibril formation were determined (9Teplow D.B. Amyloid. 1998; 5: 121-142Crossref PubMed Scopus (287) Google Scholar). However, continuing elucidation of this ostensibly classical polymerization process revealed unexpected complexity in the numbers and types ("on-pathway" or "off-pathway" for fibril formation) of assembly paths and the structures resulting therefrom (Fig. 1C and supplemental Table S1).Protofibrils, Paranuclei, and Monomer FoldsFig. 1C illustrates one pathway of fibril assembly. The penultimate fibril intermediate, the protofibril, was first identified more than a decade ago (10Caughey B. Lansbury P.T. Annu. Rev. Neurosci. 2003; 26: 267-298Crossref PubMed Scopus (1433) Google Scholar). Protofibrils were described as beaded chains, each bead of which was ∼5 nm in diameter. The length of these structures generally was <150 nm. Kinetics and solution-phase AFM experiments showed that protofibrils matured into fibrils (10Caughey B. Lansbury P.T. Annu. Rev. Neurosci. 2003; 26: 267-298Crossref PubMed Scopus (1433) Google Scholar). To understand how protofibrils formed, methods were developed to determine quantitatively the oligomer size distribution in nascent Aβ preparations (11Bitan G. Teplow D.B. Acc. Chem. Res. 2004; 37: 357-364Crossref PubMed Scopus (174) Google Scholar). In Aβ42 assembly, these experiments suggested that a pentamer or hexamer, the "paranucleus," was the basic unit of the protofibril and that the beaded chains comprising protofibrils formed by the self-association of paranuclei.To understand the oligomerization process in atomic detail, computer simulations have been done (12Urbanc B. Cruz L. Yun S. Buldyrev S.V. Bitan G. Teplow D.B. Stanley H.E. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 17345-17350Crossref PubMed Scopus (295) Google Scholar). These studies yielded oligomer frequency distributions similar to those determined experimentally, but in addition provided high resolution conformational information. Aβ40 oligomers were more compact than Aβ42 oligomers due to increased conformational freedom of the Aβ42 N termini. This suggested that intermolecular interactions among Aβ42 N termini might facilitate the C-terminal interactions obligatory for fibril formation. The work also revealed the formation of a turn in Aβ42 at Gly37-Gly38 that was not observed in Aβ40 and that thus could be critical in paranucleus formation.The importance of the C terminus of Aβ in controlling Aβ assembly has also been revealed in experiments involving amino acid substitutions (11Bitan G. Teplow D.B. Acc. Chem. Res. 2004; 37: 357-364Crossref PubMed Scopus (174) Google Scholar). Systematic alterations in residue 41 side chain hydrophobicity showed that Gly or Ala largely eliminated paranucleus formation, whereas amino acids with hydropathic characteristics similar to Ile had no effect. Elimination of the Ala42 side chain blocked paranucleus self-association, whereas insertion of larger apolar side chains facilitated the process. Similar studies examined Met35 polarity, an important question with respect to redox chemistry in AD (5Finder V.H. Glockshuber R. Neurodegener. Dis. 2007; 4: 13-27Crossref PubMed Scopus (253) Google Scholar, 11Bitan G. Teplow D.B. Acc. Chem. Res. 2004; 37: 357-364Crossref PubMed Scopus (174) Google Scholar). In these experiments, oxidation of Met35 to Met35(O) or Met35 sulfone had no effect on Aβ40 oligomerization, whereas Aβ42 paranucleus formation was abolished. Interestingly, the modified Aβ42 peptides oligomerized identically to Aβ40.The relative importance of the C terminus in controlling Aβ assembly was also apparent in studies of Aβ40 and Aβ42 peptides containing substitutions linked to familial forms of AD or CAA. These substitutions (Glu22 → Gln, Glu22 → Gly, Glu22 → Lys, and Asp23 → Asn) produced oligomers of higher order when substituted in Aβ40 but had little effect on Aβ42 oligomerization. Removal of N-terminal residues Asp1–Gly9 in Aβ42 had no effect on its oligomer size distribution, whereas truncation of either the N-terminal two or four residues of Aβ40 produced higher-order oligomers. This observation was consistent with the aforementioned simulation data that suggested that collapse of the N terminus of Aβ40 on the oligomer surface might shield underlying hydrophobic regions of the oligomers that otherwise might interact to form higher-order assemblies (12Urbanc B. Cruz L. Yun S. Buldyrev S.V. Bitan G. Teplow D.B. Stanley H.E. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 17345-17350Crossref PubMed Scopus (295) Google Scholar). In fact, this process was observed in studies of the folding and assembly of urea-denatured Aβ (13Chen Y.-R. Glabe C.G. J. Biol. Chem. 2006; 281: 24414-24422Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar). Aβ40 formed an unstable but largely collapsed monomeric species, whereas Aβ42 existed in a trimeric or tetrameric state (13Chen Y.-R. Glabe C.G. J. Biol. Chem. 2006; 281: 24414-24422Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar).The solvent inaccessibility of the Ala21–Ala30 region of Aβ likely results from the formation of a turn-like structure that nucleates monomer folding (14Teplow D.B. Lazo N.D. Bitan G. Bernstein S. Wyttenbach T. Bowers M.T. Baumketner A. Shea J.-E. Urbanc B. Cruz L. Borreguero J. Stanley H.E. Acc. Chem. Res. 2006; 39: 635-645Crossref PubMed Scopus (192) Google Scholar). This decapeptide region initially was identified due to its resistance to proteolysis, a resistance that remained in the isolated decapeptide itself and that allowed NMR and computational determinations of its structure and dynamics (14Teplow D.B. Lazo N.D. Bitan G. Bernstein S. Wyttenbach T. Bowers M.T. Baumketner A. Shea J.-E. Urbanc B. Cruz L. Borreguero J. Stanley H.E. Acc. Chem. Res. 2006; 39: 635-645Crossref PubMed Scopus (192) Google Scholar). Most recently, thermodynamics studies showed that the turn is destabilized by amino acid substitutions that cause AD and CAA (15Grant M.A. Lazo N.D. Lomakin A. Condron M.M. Arai H. Yamin G. Rigby A.C. Teplow D.B. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 16522-16527Crossref PubMed Scopus (103) Google Scholar). Destabilization correlates with accelerated Aβ oligomerization and higher-order assembly and thus provides a mechanistic explanation for these familial forms of AD and CAA.Other Assembly PathwaysThe idea that an Aβ hexamer building block exists is intriguing because at least four other structures, ADDLs, Aβ*56, "globulomers," and "Aβ oligomers," comprise multiples of this basic unit (Fig. 1C and supplemental Table S1). ADDLs are dodecamers produced in vitro from Aβ42 using special solvent conditions and appear in AFM studies as globular structures with heights of 5–6 nm (16Lambert M.P. Barlow A.K. Chromy B.A. Edwards C. Freed R. Liosatos M. Morgan T.E. Rozovsky I. Trommer B. Viola K.L. Wals P. Zhang C. Finch C.E. Krafft G.A. Klein W.L. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6448-6453Crossref PubMed Scopus (3082) Google Scholar). Aβ*56 was identified in SDS extracts from brains of Tg2576 transgenic mice (17Lesné S. Koh M.T. Kotilinek L. Kayed R. Glabe C.G. Yang A. Gallagher M. Ashe K.H. Nature. 2006; 440: 352-357Crossref PubMed Scopus (2404) Google Scholar). The "56" refers to the molecular weight of the oligomer, which is consistent with that of a dodecamer. The morphology of Aβ*56 is a prolate ellipsoid. A third type of dodecamer is the globulomer (so-called because it is a globular oligomer), which is formed by Aβ42 in the presence of SDS (18Gellermann G.P. Byrnes H. Striebinger A. Ullrich K. Mueller R. Hillen H. Barghorn S. Neurobiol. Dis. 2008; 30: 212-220Crossref PubMed Scopus (98) Google Scholar). Protease digestion, antibody binding, and mass spectrometry studies of globulomers suggest a structural model in which the hydrophobic C terminus (residues 24–42) forms a stable core and the more hydrophilic N terminus is on the surface. Although globulomers have substantial β-sheet content, presumably at the C terminus, they do not form fibrils and thus may be considered an off-pathway assembly (18Gellermann G.P. Byrnes H. Striebinger A. Ullrich K. Mueller R. Hillen H. Barghorn S. Neurobiol. Dis. 2008; 30: 212-220Crossref PubMed Scopus (98) Google Scholar). A larger species, the Aβ oligomer, also has been produced in vitro (19Deshpande A. Mina E. Glabe C. Busciglio J. J. Neurosci. 2006; 26: 6011-6018Crossref PubMed Scopus (441) Google Scholar). Its molecular weight (∼90,000) suggests that its assembly order is ∼15–20, consistent with that of an octadecamer. In addition to assemblies with globular morphology, annular pore-like structures with diameters of 8–12 nm and pore sizes of 2–2.5 nm also have been described (10Caughey B. Lansbury P.T. Annu. Rev. Neurosci. 2003; 26: 267-298Crossref PubMed Scopus (1433) Google Scholar, 20Haass C. Selkoe D.J. Nat. Rev. Mol. Cell Biol. 2007; 8: 101-112Crossref PubMed Scopus (3811) Google Scholar).The largest globular assemblies are amylospheroids and β-amyloid balls. Amylospheroids are off-pathway spheroidal structures with diameters of 10–15 nm that are formed by Aβ40 or Aβ42 (21Hoshi M. Sato M. Matsumoto S. Noguchi A. Yasutake K. Yoshida N. Sato K. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 6370-6375Crossref PubMed Scopus (436) Google Scholar). β-Amyloid balls are very large (20–200 μm) spheroidal structures formed only by Aβ40 at high concentration (300–600 μm) (22Westlind-Danielsson A. Arnerup G. Biochemistry. 2001; 40: 14736-14743Crossref PubMed Scopus (57) Google Scholar). Although such concentrations are non-physiological with respect to the average concentration of soluble Aβ in vivo, β-amyloid balls may be an interesting model of amyloid plaques or of the inclusion bodies formed in Parkinson and Huntington diseases and in the transmissible spongiform encephalopathies.Assembly Complexity and ProvenanceThe complexity of Aβ assembly complicates the determination of precursor-product relationships. For example, are the different dodecameric assemblies discussed above really different, or are they all the same entity described in different ways by different investigators? Do the different larger spheroidal assemblies form from the same hexamer building blocks that produce dodecamers and thus belong on the same pathway? We do not know, but the answers to these questions are important because they have implications for the development of therapeutic agents targeting critical steps in the assembly pathways. For example, recent work has shown that compounds exist that can efficiently inhibit fibril formation or oligomerization, but not both (23Necula M. Kayed R. Milton S. Glabe C.G. J. Biol. Chem. 2007; 282: 10311-10324Abstract Full Text Full Text PDF PubMed Scopus (595) Google Scholar). The distinction is critical if one assembly is benign and the other toxic.Aβ Assembly and DiseaseThus far, we have discussed basic aspects of the physical biochemistry of Aβ assembly. However, the most fundamental biological question is, "what is the relationship between Aβ assemblies and AD?" Strong linkage exists between amyloid formation per se and disease (for a comprehensive review, see Ref. 24Sipe J.C. Amyloid Proteins: The Beta Sheet Conformation and Disease. Wiley-VCH, Weinheim, Germany2005Crossref Scopus (22) Google Scholar), and this linkage formed, in part, the foundation for the "amyloid cascade hypothesis," which posited that amyloid fibril formation was the key pathogenetic process in AD (25Hardy J. Ann. Med. 1996; 28: 255-258Crossref PubMed Scopus (60) Google Scholar). As discussed above, elucidation of the mechanisms of fibril formation unexpectedly revealed a broad range of fibrillar and nonfibrillar structures (supplemental Table S1). Aβ oligomers appear to be particularly important because they are potent neurotoxins and are isolable from AD patients, and their concentrations correlate positively with neuropathology in vivo. These facts have produced a fundamental paradigm shift resulting in a revised amyloid cascade hypothesis (1Kirkitadze M.D. Bitan G. Teplow D.B. J. Neurosci. Res. 2002; 69: 567-577Crossref PubMed Scopus (503) Google Scholar, 20Haass C. Selkoe D.J. Nat. Rev. Mol. Cell Biol. 2007; 8: 101-112Crossref PubMed Scopus (3811) Google Scholar, 26Hardy J. Selkoe D.J. Science. 2002; 297: 353-356Crossref PubMed Scopus (10796) Google Scholar), one that posits the primacy of oligomeric forms of Aβ in AD causation.A substantial experimental corpus exists demonstrating that "Aβ" is neurotoxic (27Yankner B.A. Lu T. J. Biol. Chem. 2009; 284: 4755-4759Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar). However, it was not until approximately a decade ago, with the discovery and characterization of protofibrils and ADDLs, that a more structurally precise definition of Aβ could be made, one that in turn enabled more precise structure-neurotoxicity correlations to be established (16Lambert M.P. Barlow A.K. Chromy B.A. Edwards C. Freed R. Liosatos M. Morgan T.E. Rozovsky I. Trommer B. Viola K.L. Wals P. Zhang C. Finch C.E. Krafft G.A. Klein W.L. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6448-6453Crossref PubMed Scopus (3082) Google Scholar, 28Walsh D.M. Hartley D.M. Kusumoto Y. Fezoui Y. Condron M.M. Lomakin A. Benedek G.B. Selkoe D.J. Teplow D.B. J. Biol. Chem. 1999; 274: 25945-25952Abstract Full Text Full Text PDF PubMed Scopus (979) Google Scholar). Each new assembly subsequently discovered also was toxic. An important goal of current research is to better define the mechanisms of this toxicity, a variety of which we now discuss.Membrane EffectsAβ is an amphipathic peptide (Fig. 1A). The side chains of 16 of the first 28 residues are polar; 12 are charged at neutral pH. The remaining 12 (Aβ40) or 14 (Aβ42) side chains are apolar. Structures such as these can form micelles (29Lomakin A. Chung D.S. Benedek G.B. Kirschner D.A. Teplow D.B. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 1125-1129Crossref PubMed Scopus (730) Google Scholar) or interact with membranes directly. Recent work has shown that Aβ40 inserts into membranes of hippocampal neurons from AD brains (30Verdier Y. Zarndi M. Penke B. J. Pept. Sci. 2004; 10: 229-248Crossref PubMed Scopus (236) Google Scholar). Membrane insertion can perturb plasma membrane structure and function. For example, conformational analysis of the C-terminal domain of Aβ (residues 29–40/2) has shown it to have properties similar to those of fusion peptides of viral proteins. Insertion of these fragments in a tilted manner in the membrane is thought to disrupt the parallel symmetry of the fatty acyl chains, altering the curvature of the membrane surface and destabilizing the membrane. Consistent with this prediction, Aβ(22–42) induces membrane fusion and permeabilizes lipid vesicles that mimic neuronal membranes (31Arispe N. Diaz J.C. Simakova O. Biochim. Biophys. Acta. 2007; 1768: PubMed Scopus Google oligomers have also been shown to the of lipid and membranes by the by increasing the membrane structural or the membrane the Y. Kayed R. A. Glabe C. J. 2006; PubMed Scopus Google Scholar). These may be to of membrane and which in turn may to and (30Verdier Y. Zarndi M. Penke B. J. Pept. Sci. 2004; 10: 229-248Crossref PubMed Scopus (236) Google Scholar, Y. R. S. G. M. T. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google membrane may also Aβ40 oligomers form in neuronal plasma membranes and (30Verdier Y. Zarndi M. Penke B. J. Pept. Sci. 2004; 10: 229-248Crossref PubMed Scopus (236) Google Scholar, M. N. Y. E. Biophys. J. Full Text PDF PubMed Scopus Google Scholar). These may comprise four to each of which is an Aβ oligomer of order four to and thus the comprise a of Aβ The are that formation is a process (31Arispe N. Diaz J.C. Simakova O. Biochim. Biophys. Acta. 2007; 1768: PubMed Scopus Google Scholar). For example, (31Arispe N. Diaz J.C. Simakova O. Biochim. Biophys. Acta. 2007; 1768: PubMed Scopus Google Scholar) have shown that Aβ40 activity in lipid results in to higher AFM of have revealed structures with pore-like of and diameter. However, pore formation a that Aβ with the surface of lipid the membrane and may produce the of AFM experiments have revealed that Aβ nm in size form the of a result that could be as pore formation L. C. M. A. J. U. J. Mol. Biol. 2004; PubMed Scopus Google Scholar). Consistent with this are recent results that oligomers membrane Y. Kayed R. A. Glabe C. J. 2006; PubMed Scopus Google that two general of may structural interactions of the type discussed and specific These latter interactions may fibrillar and oligomeric forms of Aβ that either as or membrane Aβ have been identified (30Verdier Y. Zarndi M. Penke B. J. Pept. Sci. 2004; 10: 229-248Crossref PubMed Scopus (236) Google Scholar), but the important question that is these interactions are or and exists that are in the of However, this is a that We a number of mechanistic vitro results that concentrations of and can Aβ and Aβ S. S. Chem. 2007; Scopus Google Scholar, Neurosci. 2003; 26: Full Text Full Text PDF PubMed Scopus Google Scholar). Aβ has a and for and M. N. Y. E. Biophys. J. Full Text PDF PubMed Scopus Google Scholar). NMR and have suggested that the residues in Aβ, and This complex has been to chemistry which and is also thought to in this In addition to its in it has been suggested that of C. R. D. Cell. Full Text PDF PubMed Scopus Google A for redox chemistry is Met35 D.A. Curr. Med. Chem. 2003; 10: PubMed Scopus Google Scholar). The of by Aβ of or a that may the oxidation of Met35 to its or produced in this may with molecular and biological agents or to yield and the J. J. Cell Biol. 2008; 40: PubMed Scopus Google Scholar). The thus produced can further Met35 to its form and also with in a to produce Interestingly, the Met35(O) and Met35 sulfone forms of Aβ do not as the peptide (11Bitan G. Teplow D.B. Acc. Chem. Res. 2004; 37: 357-364Crossref PubMed Scopus (174) Google Scholar, L. I. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). L. I. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar) have that oxidation of Met35 to Met35(O) significantly the rate of amyloid formation and fibril Bitan and Teplow (11Bitan G. Teplow D.B. Acc. Chem. 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D.A. 2007; PubMed Scopus Google Scholar). of Aβ with a or with protein also this type of J. Dis. 2007; PubMed Scopus (98) Google common pathway of neuronal is This pathway is particularly likely to