Alzheimer Disease: Avila J

Hernández F, Avila J. · Centro de Biologi a Molecular "Severo Ochoa" (CSIC-UAM), Campus de Cantoblanco 28049 Madrid, Spain. · FEBS Lett. · Pubmed #18955053 No free full text.

Abstract: There are two different types of Alzheimers' disease, familiar Alzheimers' disease (FAD) and Sporadic Alzheimers' disease (SAD), and the origin of the disease could be different in both familial and sporadic cases. In terms of FAD, mutations in three different genes are likely to promote the onset of the disease whereas for SAD, different risk factors might be involved. Nevertheless, downstream of the initial causes of the disease some common factors may be involved. In this review, rather than the differences, we have focused on some of the common features shared by Alzheimers' patients, irrespective of the origin of their disorder. Among these common features, at the molecular level, the activation of the protein kinase GSK3 may be relevant.

Hernández F, Avila J. · Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Madrid, Spain. · J Alzheimers Dis. · Pubmed #18688097 No free full text.

Abstract: There is controversy in some neurodegenerative disorders whether the presence of aberrant aggregates in a neuron could have a toxic or a protective effect. In some disorders like in encephalopathies (prion disease), protein aggregates are toxic for the neuron. In other disorders, like Huntington disease, a protective role has been suggested for the aggregates of huntingtin. In this paper, we review the role of tau aggregation and hypothesize that tau aggregates could have an insufficient protective role in damaged neurons.

Villoslada P, Moreno B, Melero I, Pablos JL, Martino G, Uccelli A, Montalban X, Avila J, Rivest S, Acarin L, Appel S, Khoury SJ, McGeer P, Ferrer I, Delgado M, Obeso J, Schwartz M. · Department of Neuroscience, Center for Applied Medical Research, University of Navarra, Pamplona, Spain. · Clin Immunol. · Pubmed #18534912 No free full text.

Abstract: The burden of neurological diseases in western societies has accentuated the need to develop effective therapies to stop the progression of chronic neurological diseases. Recent discoveries regarding the role of the immune system in brain damage coupled with the development of new technologies to manipulate the immune response make immunotherapies an attractive possibility to treat neurological diseases. The wide repertoire of immune responses and the possibility to engineer such responses, as well as their capacity to promote tissue repair, indicates that immunotherapy might offer benefits in the treatment of neurological diseases, similar to the benefits that are being associated with the treatment of cancer and autoimmune diseases. However, before applying such strategies to patients it is necessary to better understand the pathologies to be targeted, as well as how individual subjects may respond to immunotherapies, either in isolation or in combination. Due to the powerful effects of the immune system, one priority is to avoid tissue damage due to the activity of the immune system, particularly considering that the nervous system does not tolerate even the smallest amount of tissue damage.

Engel T, Goñi-Oliver P, Gómez de Barreda E, Lucas JJ, Hernández F, Avila J. · Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Facultad de Ciencias, Universidad Autónoma de Madrid, Madrid, Spain. · Neurodegener Dis. · Pubmed #18322403 No free full text.

Abstract: Alzheimer's disease is characterized by the presence of two histopathological aberrant structures, the senile plaques and the neurofibrillary tangles. The main component of these tangles is the cytoskeletal protein tau in hyperphosphorylated form. Since a main tau kinase is glycogen synthase kinase 3 (GSK-3), the use of specific GSK-3 inhibitors, like lithium, could be a potential therapy in Alzheimer's disease. In this short article, we have done a review on tau phosphorylation in Alzheimer's disease and other tauopathies, and on the inhibition of kinases like GSK-3, involved in tau modification.

Avila J, Hernández F. · Centro de Biología Molecular Severo Ochoa, CSIC/UAM, Fac. Ciencias, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain. · Expert Rev Neurother. · Pubmed #17997701 No free full text.

Abstract: Glycogen synthase kinase (GSK)-3 has been proposed as the link between the two histopathological hallmarks of Alzheimer's disease, the extracellular senile plaques made of beta-amyloid and the intracellular neurofibrillary tangles made of hyperphosphorylated tau. Thus, GSK-3 is one of the main tau kinases and it modifies several sites of tau protein present in neurofibrillary tangles. Furthermore, GSK-3 is able to modulate the generation of beta-amyloid as well as to respond to this peptide. The use of several transgenic models overexpressing GSK-3 has been associated with neuronal death, tau hyperphosphorylation and a decline in cognitive performance. Lithium, a widely used drug for affective disorders, inhibits GSK-3 at therapeutically relevant concentrations and has been demonstrated to prevent tau phosphorylation. In this review, we summarize all these data and discuss the potential of GSK-3 inhibitors for Alzheimer's disease therapy, as well as some of their potential problems.

Hernández F, Avila J. · Centro de Biología Molecular Severo Ochoa, CSIC/UAM, Fac. Ciencias, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain. · Cell Mol Life Sci. · Pubmed #17604998 No free full text.

Abstract: Tau is a microtubule-associated protein predominantly expressed in nerve cells that promote microtubule assembly and microtubule stabilization. Tau is a cytosolic protein mainly present in axons and involved in anterograde axonal transport. In several neurodegenerative diseases, as for example Alzheimer's disease, tau metabolism is altered. Thus, alterations in the amount of the tau protein, missense mutations, posttranscriptional modifications like phosphorylation, aberrant tau aggregation or a different expression of some of its isoforms could provoke pathological effects resulting in the appearance of neuronal disorders known as tauopathies. The purpose of this work is to review the possible mechanisms for tau alterations that could lead to the onset of tau pathology. First we will focus on tau turnover, then on tau phosphorylation and, finally, on tau aggregation.

Zhu X, Avila J, Perry G, Smith MA. · Department of Pathology, Case Western Reserve University, 2103 Cornell Rd., Cleveland, OH 44106, USA. · Am J Pathol. · Pubmed #17456753 links to  free full text

This publication has no abstract.

Pevalova M, Filipcik P, Novak M, Avila J, Iqbal K. · Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia. · Bratisl Lek Listy. · Pubmed #17262986 No free full text.

Abstract: Microtubule-associated protein tau is a phosphoprotein whose expression and phosphorylation is developmentally regulated. Whereas in adult mammalian brain several isoforms are produced from a single gene by alternative splicing, in fetal brain only a single isoform exists, corresponding to the smallest of the tau isoforms. Main physiological function of tau is the promotion of assembly and stabilization of microtubular network, which is essential for normal axonal transport of vesicles within the neuron. In human, tau protein undergoes several posttranslational modifications: such as phosphorylation, truncation, nitration, glycation, glycosylation, ubiquitination and polyaminations. When these modifications are disturbed, they play a serious role during the pathogenesis of Alzheimer's disease (AD). Hyperphosphorylation and truncation as the early events in AD pathogenesis, play significant role in the formation of neurofibrillary pathology. Phosphorylated tau has reduced capability in binding to microtubules and hyperphosphorylation together with truncation contributes to the formation of pathological tau filaments. This leads to destabilization of microtubular network and subsequent impairment of microtubule associated axonal transport. Since many data suggest that sporadic AD is the "disease of posttranslational modifications" of tau protein, more detailed investigation of tau protein modifications is urgently needed in order to understand pathogenesis of sporadic Alzheimer's disease (Fig. 1, Ref. 86).

Avila J. · Centro de Biología Molecular Severo Ochoa (CSIC-UAM). Facultad de Ciencias, Campus de Cantoblanco, Universidad Autónoma de Madrid, 28049 - Madrid. Spain. · J Alzheimers Dis. · Pubmed #16914856 No free full text.

Abstract: In this volume we commemorate the centennial of Alois Alzheimer's discovery of what was later known as Alzheimer's disease, named by Alzheimer's mentor, Emil Kraepelin. In a much more low level, our group remember in this issue a paper published twenty years ago. In that paper it was described that tau can self-polymerize and, at that time, it suggested that tau was not only a component of Alzheimer paired helical filaments, as indicated some months earlier during that year, 1986, but that it was the main component of Alzheimer paired helical filaments.

Avila J. · Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, Universidad Autónoma de Madrid, 28049 Madrid, Spain. · FEBS Lett. · Pubmed #16529745 No free full text.

Abstract: In this article I shall review how tau phosphorylation and aggregation participates in Alzheimer's disease (AD) and other tauopathies. Tau, a microtubule associated protein, is the main component, in phosphorylated form, of the aberrant paired helical filaments found in AD. Tau is present in phosphorylated and aggregated form not only in AD, but in other pathologies (tauopathies). In this review, the phosphorylation of tau, its aggregation, and the possible relation between tau phosphorylation and aggregation is, briefly, described. Also, it is discussed the toxicity of modified tau. In addition, I propose a working model detailing the progression of tau pathologies.

Hernández F, Engel T, Gómez-Ramos A, Pérez M, Avila J. · Centro de Biología Molecular "Severo Ochoa," Facultad de Ciencias, Universidad Autónoma de Madrid, Madrid, 28049 Spain. · Microsc Res Tech. · Pubmed #16103994 No free full text.

Abstract: We show how electron microscopy can be used to answer several critical issues in neurodegenerative disorders that course with the formation of aberrant filamentous structures. Thus, electron microscopy is a useful technique to study in vitro assembly of pathogenic proteins, to map the regions involved in filament formation, as well as to detect by immunoelectron microscopy which proteins bind to the filaments. Furthermore, electron microscopy is the main technique used to discover if an animal model develops fibrillar pathology and if those filaments are similar to those found in human patients. This review focuses on Alzheimer's disease and related tauopathies, although similar studies have been done with other neurodegenerative disorders as, for example, Huntington's disease.

Ferrer I, Gomez-Isla T, Puig B, Freixes M, Ribé E, Dalfó E, Avila J. · Institut de Neuropatologia, Servei Anatomia Patològica, Hospital de Bellvitge, Universitat de Barcelona, Hospitalet de Llobregat, Spain. · Curr Alzheimer Res. · Pubmed #15977985 No free full text.

Abstract: Hyperphosphorylation and accumulation of tau in neurons (and glial cells) is one the main pathologic hallmarks in Alzheimer's disease (AD) and other tauopathies, including Pick's disease (PiD), progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease and familial frontotemporal dementia and parkinsonism linked to chromosome 17 due to mutations in the tau gene (FTDP-17-tau). Hyperphosphorylation of tau is regulated by several kinases that phosphorylate specific sites of tau in vitro. GSK-3-immunoprecipitated sarcosyl-insoluble fractions in AD have the capacity to phosphorylate recombinant tau. In addition, GSK-3 phosphorylated at Ser9, that inactivates GSK-3, is found in the majority of neurons with neurofibrillary tangles and dystrophic neurites of senile plaques in AD, and in Pick bodies and other phospho-tau-containing neurons and glial cells in other tauopathies. Increased expression of active kinases, including stress-activated kinase, c-Jun N-terminal kinase (SAPK/JNK) and kinase p38 has been found in brain homogenates in all the tauopathies. Strong active SAPK/JNK and p38 immunoreactivity has been observed restricted to neurons and glial cells containing hyperphosphorylated tau, as well as in dystrophic neurites of senile plaques in AD. Moreover, SAPK/JNK- and p38-immunoprecipitated sub-cellular fractions enriched in abnormal hyperphosphorylated tau have the capacity to phosphorylate recombinant tau and c-Jun and ATF-2 which are specific substrates of SAPK/JNK and p38 in AD and PiD. Interestingly, increased expression of phosphorylated (active) SAPK/JNK and p38 and hyperphosphorylated tau containing neurites have been observed around betaA4 amyloid deposits in the brain of transgenic mice (Tg 2576) carrying the double APP Swedish mutation. These findings suggest that betaA4 amyloid has the capacity to trigger the activation of stress kinases which, in turn, phosphorylate tau in neurites surrounding amyloid deposits. Complementary findings have been reported from the autopsy of two AD patients who participated in an amyloid-beta immunization trial and died during the course of immunization-induced encephalitis. The neuropathological examination of the brain showed massive focal reduction of amyloid plaques but not of neurofibrillary degeneration. Activation of SAPK/JNK and p38 were reduced together with decreased tau hyperphosphorylation of aberrant neurites in association with decreased amyloid plaques in both Tg2576 mice and human brains. These findings support the amyloid cascade hypothesis of tau phosphorylation mediated by stress kinases in dystrophic neurites of senile plaques but not that of neurofibrillary tangles and neuropil threads in AD.

Avila J, Pérez M, Lucas JJ, Gómez-Ramos A, Santa María I, Moreno F, Smith M, Perry G, Hernández F. · Centro de Biología Molecular "Severo Ochoa", Facultad de Ciencias, Campus de Cantoblanco, Universidad Autónoma de Madrid, 28049 - Madrid, Spain. · Curr Alzheimer Res. · Pubmed #15975073 No free full text.

Abstract: Tau is a microtubule associated protein that is also the main component of the aberrant filaments that form aberrant structures like the neuropil threads or the neurofibrillary tangles, found in the brain of Alzheimer's disease patients. The assembly of tau aberrant filaments could be reproduced in vitro by using a high concentration of tau protein or, at lower protein concentrations, by adding some compounds like polyanions, fatty acids (and derivates), and others. In this mini-review a descriptive analysis of the different conditions needed for in vitro tau polymerization are summarized.

Zhu X, Lee HG, Casadesus G, Avila J, Drew K, Perry G, Smith MA. · Institute of Pathology, Case Western Reserve University, Cleveland, OH, USA. · Mol Neurobiol. · Pubmed #15953822 No free full text.

Abstract: Oxidative stress is a striking feature of susceptible neurons in the Alzheimer's disease brain. Importantly, because oxidative stress is an early event in Alzheimer's disease, proximal to the development of hallmark pathologies, it likely plays an important role in the pathogenesis of the disease. Investigations into the cause of such oxidative stress show that interactions between abnormal mitochondria and disturbed metal metabolism are, at least in part, responsible for cytoplasmic oxidative damage observed in these susceptible neurons, which could ultimately lead to their demise. Oxidative stress not only temporally precedes the pathological lesions of the disease but could also contribute to their formation, which, in turn, could provide some protective mechanism to reduce oxidative stress and ensure that neurons do not rapidly succumb to oxidative insults. In this review, we present the evidence for oxidative stress in Alzheimer's disease and its likely sources and consequence in relation to other pathological changes.

Liu Q, Lee HG, Honda K, Siedlak SL, Harris PL, Cash AD, Zhu X, Avila J, Nunomura A, Takeda A, Smith MA, Perry G. · Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, Ohio 44106, USA. · Biochim Biophys Acta. · Pubmed #15615639 No free full text.

Abstract: Fibrillogenesis is a major feature of Alzheimer's disease (AD) and other neurodegenerative diseases. Fibers are correlated with disease severity and they have been implicated as playing a direct role in disease pathophysiology. In studies of tau, instead of finding causality with tau fibrils, we found that tau is associated with reduction of oxidative stress. Biochemical findings show that tau oxidative modifications are regulated by phosphorylation and that tau found in neurofibrillary tangles is oxidatively modified, suggesting that tau is closely linked to the biology, not toxicity, of AD.

Avila J. · Centro de Biología Molecular Severo Ochoa, Facultad de Ciencias, Campus de Cantoblanco, Universidad Autónoma de Madrid, 28049 Madrid, Spain. · Arch Immunol Ther Exp (Warsz). · Pubmed #15577742 No free full text.

Abstract: In this short review, the link between aging and the onset of Alzheimer 's disease is discussed. It has been widely suggested that aging is the greatest risk factor for Alzheimer 's disease,in which a failure in the insulin signal-transduction pathway could occur with age and, thereby, the assembly of senile plaques and neurofibrillary tangles (two aberrant structures present in Alzheimer 's disease)could be promoted. The main component of neurofibrillary tangles is the microtubule-associated protein tau, and the assembly of tau protein appears to occur after its modification by phosphorylation. In this phosphorylation, some protein kinases related to the insulin-transduction pathway could play a role.

Takeda A, Itoyama Y, Kimpara T, Zhu X, Avila J, Dwyer BE, Perry G, Smith MA. · Department of Neurology, Tohoku University School of Medicine, Sendai 980-8574, Japan. · Antioxid Redox Signal. · Pubmed #15345149 No free full text.

Abstract: Heme oxygenase, the rate-limiting step in heme catabolism, appears to play an important role in a number of neurodegenerative disorders, such as Alzheimer disease. Interestingly, the spatial distribution of heme oxygenase-1 expression in diseased brain is essentially identical to that of the pathological expression of tau, suggesting a key role for both in disease progression. Like heme oxygenase, the expression, phosphorylation, and aggregation of tau are regulated through signal cascades, including the extracellular signal-regulated kinases, whose activities are modulated by oxidative stress. Therefore, the expression of tau and heme oxygenase-1 in a coordinated manner likely plays a pivotal role in the cytoprotection of neuronal cells. This places heme oxygenase at the center of disease pathogenesis and offers a novel therapeutic approach targeted at either the causes or consequences of enzyme induction.

Gómez-Ramos A, Smith MA, Perry G, Avila J. · Centro de Biología Molecular, (CSIC/UAM), Facultad de Ciencias, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain. · Acta Neurobiol Exp (Wars). · Pubmed #15190678 links to  free full text

Abstract: Neurofibrillary tangles, one of the aberrant structures found in the brain of Alzheimer's disease patients are mainly composed of tau in hyperphosphorylated form. Thus, a possible relation between phosphorylation and assembly of tau proteins has been analysed. By doing in vitro studies we have observed that in certain conditions, where compounds from oxidative stress are present, the capacity of tau for self assembly increases upon phosphorylation.

Bhat RV, Budd Haeberlein SL, Avila J. · AstraZeneca R & D, Södertälje, B213:231B, Sweden 151-85. · J Neurochem. · Pubmed #15189333 No free full text.

Abstract: Abstract Glycogen synthase kinase3 (GSK3) is emerging as a prominent drug target in the CNS. The most exciting of the possibilities of GSK3 lies within the treatment of Alzheimer's disease (AD) where abnormal increases in GSK3 levels and activity have been associated with neuronal death, paired helical filament tau formation and neurite retraction as well as a decline in cognitive performance. Abnormal activity of GSK3 is also implicated in stroke. Lithium, a widely used drug for affective disorders, inhibits GSK3 at therapeutically relevant concentrations. Thus while the rationale remains testable, pharmaceutical companies are investing in finding a selective inhibitor of GSK3. In the present review, we summarize the properties of GSK3, and discuss the potential for such a therapy in AD, and other CNS disorders.

Perry G, Taddeo MA, Nunomura A, Zhu X, Zenteno-Savin T, Drew KL, Shimohama S, Avila J, Castellani RJ, Smith MA. · Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, Ohio 44106, USA. · Comp Biochem Physiol C Toxicol Pharmacol. · Pubmed #12458179 No free full text.

Abstract: In this review, we consider comparative aspects of the biology and pathology of oxygen radicals in neurodegenerative disease and how these findings have influenced our concept of oxidative stress. The common definition of oxidative stress is a breach of antioxidant defenses by oxygen radicals leading to damage to critical molecules and disrupted physiology. Inherent in this definition is that oxidative stress is an unstable situation, for if there is net damage, viability of the system decreases with time, leading to disequilibria and death. While this circumstance defines acute conditions, such as stroke and head trauma which result in dysfunction and death, it does not fit physiological situations or chronic diseases closely aligned to normal physiology. Therefore, we propose that oxidative modifications in Alzheimer disease may actually serve as a homeostatic response to stress resulting in a shift of neuronal priority from normal function to basic survival. This phenomenon is comparable to normal physiological conditions of metabolic decrease, such as those seen in hibernation and estivation. Thus, Alzheimer disease could be seen as part of normal aging that includes additional pathology due to inadequate homeostatic response.

Perry G, Nunomura A, Cash AD, Taddeo MA, Hirai K, Aliev G, Avila J, Wataya T, Shimohama S, Atwood CS, Smith MA. · Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. · J Neural Transm Suppl. · Pubmed #12456052 No free full text.

Abstract: Over the past decade, oxidative stress has been established as the earliest cytological feature of Alzheimer disease and an attractive therapeutic target. The major challenges now are establishing the source of the reactive oxygen and what oxidative stress tells us about the etiology of Alzheimer disease. These are complex issues since a variety of enzymatic and non-enzymatic processes are involved in reactive oxygen formation and damage to macromolecules. In this review, we consider disease mechanisms that show the greatest promise for future research.

Perry G, Nunomura A, Hirai K, Zhu X, Pérez M, Avila J, Castellani RJ, Atwood CS, Aliev G, Sayre LM, Takeda A, Smith MA. · Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. · Free Radic Biol Med. · Pubmed #12446204 No free full text.

Abstract: In less than a decade, beginning with the demonstration by Floyd, Stadtman, Markesbery et al. of increased reactive carbonyls in the brains of patients with Alzheimer's disease (AD), oxidative damage has been established as a feature of the disease. Here, we review the types of oxidative damage seen in AD, sites involved, possible origin, relationship to lesions, and compensatory changes, and we also consider other neurodegenerative diseases where oxidative stress has been implicated. Although much data remain to be collected, the broad spectrum of changes found in AD are only seen, albeit to a lesser extent, in normal aging with other neurodegenerative diseases showing distinct spectrums of change.

Hernández F, Lim F, Lucas JJ, Pérez-Martín C, Moreno F, Avila J. · Centro de Biología Molecular Severo Ochoa, CSIC/UAM. Madrid, Spain. · Mini Rev Med Chem. · Pubmed #12369957 No free full text.

Abstract: The deposit of two proteins in the brain characterizes Alzheimer's disease: deposits of beta-amyloid protein to form senile plaques and tau protein in neurofibrillary tangles. This review discusses transgenic animals overexpressing normal or mutated tau protein as well as kinases involved in tau hyperphosphorylation. These animals hold a great potential as tools to test the effects of forthcoming therapeutical agents for Alzheimer's disease.

Alvarez G, Muñoz-Montaño JR, Satrústegui J, Avila J, Bogónez E, Díaz-Nido J. · Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, Madrid, Spain, 28049. · Bipolar Disord. · Pubmed #12180271 No free full text.

Abstract: Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of the beta-amyloid peptide and the hyperphosphorylation of the tau protein, among other features. The most widely accepted hypothesis on the etiopathogenesis of this disease proposes that the aggregates of the beta-amyloid peptide are the main triggers of tau hyperphosphorylation and the subsequent degeneration of affected neurons. In support of this view, fibrillar aggregates of synthetic beta-amyloid peptide induce tau hyperphosphorylation and cell death in cultured neurons. We have previously reported that lithium inhibits tau hyperphosphorylation and also significantly protects cultured neurons from cell death triggered by beta-amyloid peptide. As lithium is a relatively specific inhibitor of glycogen synthase kinase-3 (in comparison with other protein kinases), and other studies also point to a relevant role of this enzyme, we favor the view that glycogen synthase kinase-3 is a crucial element in the pathogenesis of Alzheimer's disease. In our opinion, the possibility of using lithium, or other inhibitors of glycogen synthase kinase-3, in experimental trials aimed to ameliorate neurodegeneration in Alzheimer's disease should be considered.

Díaz-Nido J, Wandosell F, Avila J. · Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, 28049 Madrid, Spain. · Peptides. · Pubmed #12128089 No free full text.

Abstract: Protein aggregation into dense filamentous inclusions is a characteristic feature of many etiologically diverse neurodegenerative disorders including Alzheimer's disease (AD), spongiform encephalopathies, and tauopathies. Thus, beta-amyloid peptide (Abeta) accumulates within senile amyloid plaques in AD, protease-resistant prion protein constitutes the amyloid deposits in spongiform encephalopathies and tau protein gives rise to neurofibrillary tangles (NFT) both in AD and in tauopathies. Curiously, these abnormal protein inclusions contain, in addition to their major peptide components, some associated sulfated glycosaminoglycans (sGAG). Here we discuss the proposal that the binding of sGAG to aggregate-forming peptides may modify the pathogenic process depending on their subcellular localization.