Amyloid fibrils in neurodegenerative diseases: villains or heroes?

Abstract

Future Medicinal ChemistryVol. 5, No. 16 EditorialFree AccessAmyloid fibrils in neurodegenerative diseases: villains or heroes?Xavier Fernàndez-BusquetsXavier Fernàndez-BusquetsInstitute for Bioengineering of Catalonia (IBEC), Baldiri Reixac 10–12, Barcelona E08028, Spain Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), Rosselló 149–153, Barcelona E08036, Spain and Nanoscience & Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, Barcelona E08028, Spain. Search for more papers by this authorEmail the corresponding author at xfernandez_busquets@ub.eduPublished Online:31 Oct 2013https://doi.org/10.4155/fmc.13.138AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: Alzheimer’s diseaseamyloid fibrilsamyloid-β peptideamyloidogenesisfunctional amyloidsglycosaminoglycanAmyloid fibrils are formed by self-aggregating polypeptides adopting a highly stable β-sheet conformation [1], whose presence correlates with severe proteinopathies that were originally identified in neurological disorders such as Alzheimer’s (AD), Parkinson’s, Huntington’s and Creutzfeldt-Jakob’s diseases, but nowadays the list has been extended to encompass many others, which include chronic hemodialysis, adult-onset diabetes, rheumatoid arthritis and inflammatory conditions. Because of the coincidence of their detection with the time of clinical diagnosis, amyloid fibrils have been traditionally seen as the culprit, but, as so frequently happens in biological systems, what initially seems to be a reasonable hypothesis, often ends up in a completely different explanation. Nowhere has this thrilling plot been more evident than in what is possibly the epitome of fibril–conformational disorder relationships: that of AD and the amyloid-β (Aβ) peptide, an approximately 42-amino acid fragment massively cleaved under pathological conditions from the endogenous amyloid precursor protein.The original amyloid cascade hypothesis of AD [2] postulated that an increase of Aβ is the initial event that unleashes neurotoxic alterations such as fibril deposition, oxidative stress, disruption of calcium homeostasis, intracellular tau protein aggregation, activation of inflammatory response and release of toxic molecules. Since Aβ fibril accumulation into extracellular deposits, termed amyloid plaques, is an early stage in the development of AD, inhibition of this process is still today usually proposed as a main therapeutic strategy. However, if the pathogenic species were a fibril precursor, blocking fibrillogenesis might accelerate the disease by facilitating the accumulation of the toxic component. Indeed, early data demonstrated that oligomers of Aβ that are intermediate species in the assembly of fibrils are powerful neurotoxins, and could therefore be the key effectors of cytotoxicity [3]. Other evidences, though, indicated that the neurotoxic activity of Aβ requires its aggregation into amyloid-containing entities [4]. These apparently contradictory observations on cytotoxic effects would be consistent with the existence of different Aβ fibril forms not so easily distinguished from each other: a highly stable fibrillar species locking toxic Aβ into its structure, and a somehow less permanent fibril type that would be a soluble peptide depot ready to be mobilized at any time [5]. Is there some rationale supporting this view?Because Aβ fibrils are found outside cells, factors that might influence their assembly should be sought after in the extracellular matrix of the brain. One of the main components of cerebral extracellular matrices are proteoglycans, large macromolecular assemblies composed of proteins and polysaccharides with various degrees of sulfation, termed glycosaminoglycans (GAGs) [6]. GAGs are found associated with plaques formed in several regions of AD brains, and have been reported to facilitate the formation of Aβ fibrils and to stabilize mature fibrils against proteolytic degradation [7]. In addition, heparan and chondroitin sulfate GAGs have been described to attenuate the neurotoxic effect of Aβ in primary neuronal cultures and in neuron-like cell lines [8], and the highly sulfated GAG heparin induces Aβ aggregation and reduces the toxicity of the peptide on cerebrovascular cells [9]. A study of the effect of several GAGs and other polysaccharides on Aβ fibril assembly shed some light on a possible mechanism that could explain both the promotion of fibrillogenesis and the reduced cytotoxicity of certain fibril types [10]. Endogenous GAGs, including those mentioned above as well as hyaluronan, which bears carboxyl instead of sulfate groups, promoted the formation of Aβ fibrils with high amyloid structure and β-sheet content that were more resistant to protease degradation than control fibrils formed in the absence of GAGs. On the other hand, the positively charged polysaccharide chitosan essentially allowed the formation of protease-sensitive short Aβ fibril precursors. Finally, fibrils of intermediate stability were obtained in the presence of the anionic synthetic polymer poly(vinyl sulfate), which carries more tightly packed negatively charged groups than GAGs. When comparing the structures of the different polysaccharides it became evident that those having anionic groups spaced by the same distance found between β-strands inside an Aβ fibril (∼4.7 Å) were promoters of stable fibril formation, whereas those polymers bearing cationic charges with the same spacing or wrongly spaced negative charges were inhibitors of well-structured fibrils.It has been proposed that GAGs may have a scaffolding role, promoting fibrillogenesis-prone conformations of the amyloid precursor proteins [11]. This template role would accelerate the formation of compact Aβ fibrils, providing them with increased stability and resistance against proteolytic degradation and microglia-mediated removal, but also against the leakage of neurotoxic soluble Aβ. Favorable electrostatic interactions through their backbone of negatively charged groups have been invoked to explain the ability of linear anionic polymers to promote the aggregation of amyloidogenic proteins [12]. Aβ and other self-aggregating peptides share cationic motifs that may be involved in binding to the negative charges of sulfated GAGs. Supportive of this view is the finding that low susceptibility of neurons and cortical areas to neurofibrillar deposition corresponds with high proportions of chondroitin sulfate proteoglycans in the neuronal microenvironment [13]. It is conceivable then that GAG-mediated neuroprotection is due to the sequestration of Aβ, in agreement with the proposal that the generation of senile plaques in AD is a protective response of the brain aimed at reducing soluble Aβ neurotoxicity [14], in what would be another example of a functional amyloid. Functional amyloids were first described in microorganisms, where they play essential roles in biofilm formation, host invasion and modulation of adhesion and surface tension for the development of aerial structures. Extracellularly found amyloid fibrils could, thus, also have a functional, as opposed to pathological, role in certain human conditions. Even intracellular amyloids such as the fibrils formed by tau proteins in AD could be involved in a beneficial function for the organism of inducing apoptosis when the cell is hopelessly deteriorated.However, other secondary actors may play important and unexpected roles. One of these obscure characters are advanced glycation end products (AGEs), highly reactive entities generated by a non-enzymatic reaction of reducing carbohydrates with amino groups, capable of crosslinking proteins, and which have been implicated in amyloid plaque deposition [15]. Some works suggest that diabetic patients have a major risk of developing AD [16], although a relationship between both pathologies has not been firmly established. An immunohistochemical study in human post-mortem samples of AD with diabetes indicated that, compared with AD, AD with diabetes brains had an increased number and size of Aβ dense plaques, receptors for AGE-positive cells, higher AGE levels and major microglial activation [17], all of them hallmarks of AD. Because in diabetes the cell reacts as in a situation of low glucose, polysaccharide stores are depleted to feed glucose biosynthetic pathways, likely resulting in reduced GAG levels. Could it be that the augmented incidence of AD in a diabetic background had something to do with a GAG-depleted extracellular matrix that would not expedite fibril formation, whereas increased AGEs crosslinked Aβ into low-order aggregates more prone to leak peptides that, hence, would act as reservoirs of toxic soluble species?Most current AD therapies are addressed to prevent Aβ fibrillogenesis, either through reduction of Aβ production, inhibition of fibril formation or removal of fibrillar aggregates [18]. Perhaps a new therapeutic strategy against AD can consist of promoting the formation of amyloid fibrils with the objective of locking soluble pernicious Aβ species into inert structures. Both approaches can be conciliated within the generally accepted view that the elimination of soluble oligomers, either by preventing their formation or by stimulating their incorporation into fibrils, can reduce Aβ cytotoxicity. Nevertheless, systemic administration of amyloid-promoting compounds can incur the risk of unspecifically promoting the formation of amyloid fibrils of a number of proteins in different parts of the body. In the case of AD therapeutics, GAG-like polymeric promoters have the added obstacle of needing to cross the blood–brain barrier, which effectively blocks the entry of such large macromolecules. Could, instead, future AD therapeutic strategies contemplate surgically implanting inside selected brain areas small nuclei coated with amyloid fibril-promoting structures that would act as Aβ ‘drains’? Once again, it will not be so simple: the accumulation of neurotoxic Aβ is likely mainly due not to increased production, but to faulty clearance from the brain [19]; because from its large systemic pool in the blood Aβ can enter the brain through the receptor for AGE, which takes it across the blood–brain barrier [20], it remains to be seen whether such Aβ attractors would not be quickly saturated, and therefore require, frequent replacement.But, of course, it might well be that highly stable fibrillar aggregates showing no cytotoxicity for in vitro cell cultures are after all deleterious for a functional brain, perhaps simply through a physical impairment of neuronal connections by constricting axons or acting as barriers for neurotransmitters in synaptic clefts. The lesson being taught to us is that nothing is only black or white, and that, especially for the particular case of Aβ and AD, we are not yet in possession of the final answer. It would probably be wise to review the physiopathology of all protein conformational disorders and look at them from the perspective of a possible therapeutic functionality in amyloid fibril formation.Financial & competing interests disclosureThis work was supported by grants BIO2011–25039 from the Ministerio de Economía y Competitividad, Spain, which included FEDER funds, and 2009SGR-760 from the Generalitat de Catalunya, Spain. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.References1 Žerovnik E, Stoka V, Mirtič A et al. Mechanisms of amyloid fibril formation: focus on domain-swapping. FEBS J.278(13),2263–2282 (2011).Crossref, Medline, CAS, Google Scholar2 Hardy JA , Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science256(5054),184–185 (1992).Crossref, Medline, CAS, Google Scholar3 Lambert MP, Barlow AK, Chromy BA et al. Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins. Proc. Natl Acad. Sci. USA95(11),6448–6453 (1998).Crossref, Medline, CAS, Google Scholar4 Serpell LC. Alzheimer’s amyloid fibrils: structure and assembly. Biochim. Biophys. Acta1502(1),16–30 (2000).Crossref, Medline, CAS, Google Scholar5 Bravo R, Arimon M, Valle-Delgado JJ et al. Sulfated polysaccharides promote the assembly of amyloid β1–42 peptide into stable fibrils of reduced cytotoxicity. J. Biol. Chem.283(47),32471–32483 (2008).Crossref, Medline, CAS, Google Scholar6 Ruoslahti E. Brain extracellular matrix. Glycobiology6(5),489–492 (1996).Crossref, Medline, CAS, Google Scholar7 McLaurin J, Franklin T, Zhang X, Deng J, Fraser PE. Interactions of Alzheimer amyloid-β peptides with glycosaminoglycans. Effects on fibril nucleation and growth. Eur. J. Biochem.266(3),1101–1110 (1999).Crossref, Medline, CAS, Google Scholar8 Fernàndez-Busquets X, Ponce J, Bravo R et al. Modulation of amyloid β peptide1–42 cytotoxicity and aggregation in vitro by glucose and chondroitin sulfate. Curr. Alzheimer Res.7(5),428–438 (2010).Crossref, Medline, CAS, Google Scholar9 Timmer NM, Schirris TJ, Bruinsma IB et al. Aggregation and cytotoxic properties towards cultured cerebrovascular cells of Dutch-mutated Aβ40 (DAβ1–40) are modulated by sulfate moieties of heparin. Neurosci. Res.66(4),380–389 (2010).Crossref, Medline, CAS, Google Scholar10 Valle-Delgado JJ, Alfonso-Prieto M, de Groot NS et al. Modulation of Aβ42 fibrillogenesis by glycosaminoglycan structure. FASEB J.24(11),4250–4261 (2010).Crossref, Medline, CAS, Google Scholar11 Ancsin JB. Amyloidogenesis: historical and modern observations point to heparan sulfate proteoglycans as a major culprit. Amyloid10(2),67–79 (2003).Crossref, Medline, CAS, Google Scholar12 Calamai M, Kumita JR, Mifsud J et al. Nature and significance of the interactions between amyloid fibrils and biological polyelectrolytes. Biochemistry45(42),12806–12815 (2006).Crossref, Medline, CAS, Google Scholar13 Brückner G, Hausen D, Hartig W, Drlicek M, Arendt T, Brauer K. Cortical areas abundant in extracellular matrix chondroitin sulphate proteoglycans are less affected by cytoskeletal changes in Alzheimer’s disease. Neuroscience92(3),791–805 (1999).Crossref, Medline, Google Scholar14 Stefani M. Structural features and cytotoxicity of amyloid oligomers: Implications in Alzheimer’s disease and other diseases with amyloid deposits. Prog. Neurobiol.99(3),226–245 (2012).Crossref, Medline, CAS, Google Scholar15 DeGroot J. The AGE of the matrix: chemistry, consequence and cure. Curr. Opin. Pharmacol.4(3),301–305 (2004).Crossref, Medline, CAS, Google Scholar16 Takeuchi M , Yamagishi S. Possible involvement of advanced glycation end-products (AGEs) in the pathogenesis of Alzheimer’s disease. Curr. Pharm. Des.14(10),973–978 (2008).Crossref, Medline, CAS, Google Scholar17 Valente T, Gella A, Fernàndez-Busquets X, Unzeta M, Durany N. Immunohistochemical analysis of human brain suggests pathological synergism of Alzheimer’s disease and diabetes mellitus. Neurobiol. Dis.37(1),67–76 (2010).Crossref, Medline, CAS, Google Scholar18 Bayer TA. Proteinopathies, a core concept for understanding and ultimately treating degenerative disorders? Eur.Neuropsychopharmacol. doi:10.1016/j.euroneuro.2013.03.007 (2013) (Epub ahead of print).Medline, Google Scholar19 Mawuenyega KG, Sigurdson W, Ovod V et al. Decreased clearance of CNS β-amyloid in Alzheimer’s disease. Science330(6012),1774–1774 (2010).Crossref, Medline, CAS, Google Scholar20 Sagare AP, Bell RD, Zlokovic BV. Neurovascular defects and faulty amyloid-β vascular clearance in Alzheimer’s disease. J. Alzheimers Dis.33(0),S87–S100 (2013).Crossref, Medline, Google ScholarFiguresReferencesRelatedDetailsCited ByThe contribution of individual residues of an aggregative hexapeptide derived from the human γD-crystallin to its amyloidogenicityInternational Journal of Biological Macromolecules, Vol. 201Aminoalkyl-substituted flavonoids: synthesis, cholinesterase inhibition, β-amyloid aggregation, and neuroprotective study23 May 2019 | Medicinal Chemistry Research, Vol. 28, No. 7Heparin: new life for an old drugNanomedicine, Vol. 12, No. 14 Vol. 5, No. 16 Follow us on social media for the latest updates Metrics History Published online 31 October 2013 Published in print October 2013 Information© Future Science LtdKeywordsAlzheimer’s diseaseamyloid fibrilsamyloid-β peptideamyloidogenesisfunctional amyloidsglycosaminoglycanFinancial & competing interests disclosureThis work was supported by grants BIO2011–25039 from the Ministerio de Economía y Competitividad, Spain, which included FEDER funds, and 2009SGR-760 from the Generalitat de Catalunya, Spain. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download