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Results for “Protein Aggregation, Pathological”

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PubMed2005

Surface-induced aggregation of beta amyloid peptide by co-substituted alkanethiol monolayers supported on gold.

The primary pathological characteristic of Alzheimer's disease is the presence in the brain of self-assembled beta amyloid (Abeta) protein fibrils, consisting of 35-43 amino acid residues. The toxicity of the aggregated protein structures has previously been proposed to be related to the interaction of Abeta fibrils with neuronal membranes (phospholipid bilayers). Here, surfaces consisting of self-assembled alkanethiol monolayers with different end groups--supported on Au--are used to test the effect of surface chemistry on the structure and morphology of aggregates formed from an active fragment (Abeta10-35) of the Abeta peptide. The influence of monolayer nature (end group) on the aggregation of Abeta10-35 was examined using reflection-absorption infrared spectroscopy (RAIRS) and scanning force microscopy (SFM). Evaluation of the SFM and RAIRS data reveals the presence of Abeta10-35 protein on the various monolayer surfaces, with the surface protein possessing predominantly beta-sheet and random-coil conformations. Time-dependent studies of the extent of Abeta10-35 aggregation and deposition on the various surfaces and the effect of the monolayers on seeding of Abeta10-35 aggregates in solution are also discussed.

Alkanes↗

PubMedDate not supplied

The possible role of the immune system in Alzheimer's disease.

Currently, there is little doubt that the immune system plays a role in the neurodegenerative process in Alzheimer's disease (AD). Inflammatory proteins such as complement components, enzymes, eicosanoids, and cytokines are found in association with cerebral amyloid plaques and may exacerbate the fundamental pathology of AD, by stimulating Amyloid beta (A beta) production, supporting its aggregation and increasing its cytotoxicity. Activated microglia and astrocytes are the main source of these proteins, and A beta may trigger their release. Interestingly, there are also indications that the immune system may play a protective role against the development of AD. Microglial cells have been shown to degrade A beta, and recent evidence suggests that autoreactive A beta-specific T cells may be relevant to the elimination of the peptide. This mechanism seems, however, impaired in the majority of patients with AD. The immune system seems thus to represent a natural line of defense against the accumulation of dangerous amyloidogenic substances. Impairment of this specific immunological defense mechanism and the failure to eliminate a toxic metabolite can be the basis for a chronic nonspecific inflammatory process in the brain, as described above. AD is a good example how an immune response initially aiming at maintaining the integrity of the body may fail and consequently lead to tissue destruction and neuronal loss.

Alzheimer Disease↗

PubMed2002

TorsinA and heat shock proteins act as molecular chaperones: suppression of alpha-synuclein aggregation.

TorsinA, a protein with homology to yeast heat shock protein104, has previously been demonstrated to colocalize with alpha-synuclein in Lewy bodies, the pathological hallmark of Parkinson's disease. Heat shock proteins are a family of chaperones that are both constitutively expressed and induced by stressors, and that serve essential functions for protein refolding and/or degradation. Here, we demonstrate that, like torsinA, specific molecular chaperone heat shock proteins colocalize with alpha-synuclein in Lewy bodies. In addition, using a cellular model of alpha-synuclein aggregation, we demonstrate that torsinA and specific heat shock protein molecular chaperones colocalize with alpha-synuclein immunopositive inclusions. Further, overexpression of torsinA and specific heat shock proteins suppress alpha-synuclein aggregation in this cellular model, whereas mutant torsinA has no effect. These data suggest that torsinA has chaperone-like activity and that the disease-associated GAG deletion mutant has a loss-of-function phenotype. Moreover, these data support a role for chaperone proteins, including torsinA and heat shock proteins, in cellular responses to neurodegenerative inclusions.

Alzheimer Disease↗

PubMed2000

Implication of novel biochemical property of beta-amyloid.

Alzheimer disease (AD) is a heterogeneous disorder with a variety of molecular pathologies converging predominantly on abnormal amyloid deposition particularly in the brain. beta-Amyloid aggregation into senile plaques is one of the pathological hallmarks of AD. beta-Amyloid is generated by a proteolytic cleavage of a large membrane protein, amyloid precursor protein (APP). We have observed a new property of beta-amyloid. The amyloid 1-42 beta fragment, when aggregated, possesses proteolytic and esterase-like activity, in vitro. Three independent methods were used to test the new property of beta-amyloid. While esterase activity involves imidazole catalysis, proteolytic activity is consistent with participation of a serine peptidase triad: catalytic Ser, His and Glu (or Asp). Although the amino acid triad is a necessary requirement for the protease reactivity, it is not sufficient since the secondary structure of the protein significantly contributes to the proteolytic activity. The ability of beta-amyloid to cleave peptide or ester bonds could be thus responsible for either inactivation of other proteins and/or APP proteolysis itself. This property may be responsible for early pathogenesis of AD since there is emerging evidence that non-plaque amyloid is elevated in Alzheimer patients.

Amyloid beta-Peptides↗

PubMed1997

Mechanisms initiating platelet thrombus formation.

The functions of platelets depend on their ability to interest with surface exposed at sites of tissue damage and then with one another after activation, thus aggregating into thrombi. This complex process, normally beneficial to arrest bleeding during hemostasis, may become a cause of catastrophic disease when it leads to thrombotic occlusion of atherosclerotic vessels curtailing arterial blood flow to vital organs. Fluid dynamic conditions modulate all aspects of platelet response to vascular injury. At higher levels of shear stress, encountered both in normal vessels during normal hemostasis or in pathological conditions of the vasculature during thrombosis, von Willebrand factor becomes the essential adhesive protein for both adhesion and aggregation. Two platelet membrane receptors, the glycoprotein complexes Ib-IX-V and IIb-IIIa (integrin alpha IIb beta 3), mediate the von Willebrand factor function in a coordinate and synergistic manner, each contributing unique biomechanical properties to support thrombus formation. The developing understanding of the structure and mechanism of action of the key adhesive domains of von Willebrand factor, as well as of their cognate cellular and extracellular binding sites, will provide solid pathophysiological foundation for the evaluation of novel anti-thrombotic strategies.

Biomechanical Phenomena↗

PubMed2006

Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice.

Point mutations in Cu, Zn-superoxide dismutase (SOD1) cause a familial form of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Aggregates of mutant SOD1 proteins are observed in histopathology and are invoked in several proposed mechanisms for motor neuronal death; however, the significant stability and activity of the mature mutant proteins are not readily explained in such models. Recent biochemical studies suggest that it is the immature disulfide-reduced forms of the familial ALS mutant SOD1 proteins that play a critical role; these forms tend to misfold, oligomerize, and readily undergo incorrect disulfide formation upon mild oxidative stress in vitro. Here we provide physiological support for this mechanism of aggregate formation and show that a significant fraction of the insoluble SOD1 aggregates in spinal cord of the ALS-model transgenic mice contain multimers cross-linked via intermolecular disulfide bonds. These insoluble disulfide-linked SOD1 multimers are found only in the spinal cord of symptomatic transgenic animals, are not observed in unafflicted tissue such as brain cortex and liver, and can incorporate WT SOD1 protein. The findings provide a biochemical basis for a pathological hallmark of this disease; namely, incorrect disulfide cross-linking of the immature, misfolded mutant proteins leads to insoluble aggregates.

Amyotrophic Lateral Sclerosis↗

PubMed2005

Can tau filaments be both physiologically beneficial and toxic?

Alzheimer's disease (AD) is a progressive disease of aging primarily characterized at the behavioral level by symptoms of memory loss. The pathological hallmarks of AD are extracellular plaques and intracellular neurofibrillary tangles that are composed of filamentous polymers of beta-amyloid (Abeta) and tau, respectively. Aggregates of filaments are not unique to AD--fibrous polymers are the pathological signatures of many diseases of aging such as Huntington's disease and Parkinson's disease. Whether Abeta or tau filaments cause AD is still an open question, as a wide variety of proteins and pathways have been implicated in the initiation and advancement of the disease--processes such as apoptosis, oxidative stress, and protein degradation. That polymers are the prevalent species observed in aging disorders suggests that this morphology of aggregation represents a significant physiological role. As a consequence of an independent insult or aging itself, the filament shifts from a physiological role to one with pathological implications. The relative importance of Abeta filaments versus tau filaments has also been a focus of significant debate within the research community. Although genetic evidence indicates that Abeta filaments are an integral component in AD, only tau pathology has been found to correlate with symptom presentation in patients. Not only do tau filaments greatly contribute to the systematic loss of neurons and the pathological presentation of memory loss, but they may represent a physiological process whose regulation may be controlled.

Aging↗

PubMed2003

Association study between Alzheimer's disease and genes involved in Abeta biosynthesis, aggregation and degradation: suggestive results with BACE1.

BACKGROUND: Amyloid beta-peptide (Abeta) biosynthesis, aggregation and degradation constitute three important steps to consider in the study of pathological mechanisms involved in Alzheimer's disease (AD). Several proteins have been suggested as involved in each of these processes: proteolytic cleavage of the amyloid precursor protein by the beta-site APP cleaving enzyme (BACE), increased amyloid fibril formation by the activity of the acetylcholinesterase (ACHE gene), and degradation of Abeta aggregates by the plasmin system have been exhaustively documented. METHODS: A case-control design was used to evaluate the possible association between candidate genes involved in these three processes and AD. We analysed three polymorphisms located at the BACE1 gene, one polymorphism at the ACHE gene, and two variants located at the tissue plasminogen activator and plasminogen activator inhibitor-1 (genes TPA and PAI- 1, respectively), both part of the plasmin system. RESULTS: We found an association between BACE1 exon 5 GG genotype and AD (age-and gender-adjusted odds ratio = 2.14, P =0.014). Although a similar association was reported previously by Nowotny and collaborators only in subjects carrying the epsilon4-allele of the apolipoprotein E gene (APOE), we did not detect this effect. However,when we combined our results with those previously reported, a clear increase of the risk to develop AD appeared in subjects carrying both the BACE1 exon 5 GG genotype and the APOE epsilon4-allele (crude OR = 2.2, P = 0.004). CONCLUSION: These data suggest a possible genetic relation between BACE1 and AD.

3' Untranslated Regions↗

PubMed2003

In vitro unfolding, refolding, and polymerization of human gammaD crystallin, a protein involved in cataract formation.

Human gammaD crystallin (HgammaD-Crys), a major protein of the human eye lens, is a primary component of cataracts. This 174-residue primarily beta-sheet protein is made up of four Greek keys separated into two domains. Mutations in the human gene sequence encoding HgammaD-Crys are implicated in early-onset cataracts in children, and the mutant protein expressed in Escherichia coli exhibits properties that reflect the in vivo pathology. We have characterized the unfolding, refolding, and competing aggregation of human wild-type HgammaD-Crys as a function of guanidinium hydrochloride (GuHCl) concentration at neutral pH and 37 degrees C, using intrinsic tryptophan fluorescence to monitor in vitro folding. Wild-type HgammaD-Crys exhibited reversible refolding above 1.0 M GuHCl. The GuHCl unfolded protein was more fluorescent than its native counterpart despite the absence of metal or ion-tryptophan interactions. Aggregation of refolding intermediates of HgammaD-Crys was observed in both equilibrium and kinetic refolding processes. The aggregation pathway competed with productive refolding at denaturant concentrations below 1.0 M GuHCl, beyond the major conformational transition region. Atomic force microscopy of samples under aggregating conditions revealed the sequential appearance of small nuclei, thin protofibrils, and fiber bundles. The HgammaD-Crys fibrous aggregate species bound bisANS appreciably, indicating the presence of exposed hydrophobic pockets. The mechanism of HgammaD-Crys aggregation may provide clues to understanding age-onset cataract formation in vivo.

Cataract↗

PubMed1998

Immunohistochemical demonstration of tissue transglutaminase in amyloid plaques.

The brain of Alzheimer's disease patients contains deposits of the 39-42-amino acid (approximately 4 kDa) amyloid beta-peptide, which is derived from the beta-amyloid precursor protein. These pathological deposits have been shown to consist in part of insoluble 8- and 16-kDa aggregates of the amyloid beta-peptide. This report confirms that the amyloid beta-peptide is a substrate for tissue transglutaminase (TGase) and demonstrates that human brain preparations from Alzheimer's disease patients and control patients form cross-linked dimers from added iodinated amyloid beta-peptide. Immunohistochemical staining for TGase revealed its presence in tissue sections and isolated amyloid plaque cores obtained from brains of patients diagnosed as having Alzheimer's disease. These results provide evidence that the previously described insoluble amyloid deposits in Alzheimer's disease may involve TGase-mediated cross-linked amyloid beta-peptide polymers, and suggest a potential role for TGase in the pathogenesis of this disease.

Aged↗

PubMed2006

Spectroscopic approaches to the conformation of tau protein in solution and in paired helical filaments.

The abnormal aggregation of the microtubule-associated protein tau into paired helical filaments is one the hallmarks of Alzheimer's disease. This aggregation is based in the partial formation of beta-structure. In contrast, the soluble protein shows a mostly random coil structure, as judged by circular dichroism, Fourier transform infrared, X-ray scattering and biochemical assays. Here, we review the basis of the natively unstructured character of tau, as well as recent studies of residual structure and long-range interactions between different domains of the protein. Analysis of the primary structure reveals a very low content of hydrophobic amino acids and a high content of charged residues, both of which tend to counteract a well-folded globular state of proteins. In the case of tau, the low overall hydrophobicity is sufficient to explain the lack of folding. This is in contrast to other proteins which also carry an excess charge at physiological pH. By tryptophan scanning mutagenesis and fluorimetry we found that most of the sequence is solvent exposed. Analysis of the hydrodynamic radii confirms a mostly random coil structure of various tau isoforms and tau domains. The proteins can be further expanded by denaturation with GdHCl which indicates some global folding. This was substantiated by a FRET-based approach where the distances between different domains of tau were determined. The combined data show that tau is mostly disordered and flexible but tends to assume a hairpin-like overall fold which may be important in the transition to a pathological aggregate.

Animals↗

PubMed2002

Imaging real-time aggregation of amyloid beta protein (1-42) by atomic force microscopy.

Amyloid beta protein (AbetaP) is the major fibrillar constituent of senile plaques. However, no causative role for AbetaP-fibers in Alzheimer's disease (AD) pathology is established. Globular AbetaPs are continuously released during normal cellular metabolism at pico- to nano-molar concentration. We used atomic force microscopy (AFM) to examine aggregation of freshly prepared AbetaP(1-42) and to examine the role of AbetaP concentration, imaging medium (air, water, or PBS) and agonists/antagonists on AbetaP-fibrillogenesis. At even very high and non-physiological AbetaP concentrations, 24-48 h of real-time AFM imaging (a) in water show only multiple layers of globular aggregates and no fibrils and (b) in PBS show mainly the globular structures and some short fibrils. On-line addition of Zn, an agonist for AbetaP-fibrillogenesis, induced a slow but non-fibrillar aggregation of globular AbetaPs. EDTA, a chelator of Zn and calcium (a modulator of AbetaP-mediated toxicity) induced a reversible change in the Zn-mediated aggregation. These results strongly suggest that no AbetaP-fibers are formed for the physiologically relevant concentration and thus the plaque-associated fibers may not account for the AD pathophysiology.

Air↗

PubMed1988

Cortical angiopathy in Alzheimer's disease: the formation of dystrophic perivascular neurites is related to the exudation of amyloid fibrils from the pathological vessels.

We studied the organization of dystrophic neurites around pathological vessels in Alzheimer cortex. Two techniques were used simultaneously on serial sections: thioflavine staining of amyloid substance and immunohistochemistry with immune sera against Paired Helical Filaments (anti-PHF) and native Tau proteins (anti-Tau). We observed different distributions of dystrophic neurites (immunolabelled with anti-PHF or anti-Tau) around thioflavine-stained angiopathic arterioles. The wall of the vessels with large diameter (greater than 100 microns) presented a congophilic angiopathy without neuropil reaction. In vessels with lesser diameter (less than 100 microns), dystrophic neurites constituted a discontinuous sleeve around vessels, always in close contact with amyloid substance outside the wall (dysphoric angiopathy). We observed structures similar to senile plaques around capillaries (diameter: 10-15 microns). The sleeve of dystrophic neurites with aggregated Tau proteins were always observed in the close vicinity of the amyloid substance which exuded from the pathological blood vessels. Thus, the exudation of these amyloid fibrils seems to induce the formation of dystrophic neurites (neuritic reaction).

Aged↗

PubMed2000

Neuroinflammatory signaling upregulation in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive, neurodestructive process of the human neocortex, characterized by the deterioration of memory and higher cognitive function. A progressive and irreversible brain disorder, AD is characterized by three major pathogenic episodes involving (a) an aberrant processing and deposition of beta-amyloid precursor protein (betaAPP) to form neurotoxic beta-amyloid (betaA) peptides and an aggregated insoluble polymer of betaA that forms the senile plaque, (b) the establishment of intraneuronal neuritic tau pathology yielding widespread deposits of agyrophilic neurofibrillary tangles (NFT) and (c) the initiation and proliferation of a brain-specific inflammatory response. These three seemingly disperse attributes of AD etiopathogenesis are linked by the fact that proinflammatory microglia, reactive astrocytes and their associated cytokines and chemokines are associated with the biology of the microtubule associated protein tau, betaA speciation and aggregation. Missense mutations in the presenilin genes PS1 and PS2, implicated in early onset familial AD, cause abnormal betaAPP processing with resultant overproduction of betaA42 and related neurotoxic peptides. Specific betaA fragments such as betaA42 can further potentiate proinflammatory mechanisms. Expression of the inducible oxidoreductase cyclooxygenase-2 and cytosolic phospholipase A2 (cPLA2) are strongly activated during cerebral ischemia and trauma, epilepsy and AD, indicating the induction of proinflammatory gene pathways as a response to brain injury. Neurotoxic metals such as aluminum and zinc, both implicated in AD etiopathogenesis, and arachidonic acid, a major metabolite of brain cPLA2 activity, each polymerize hyperphosphorylated tau to form NFT-like bundles. Further, epidemiological and longitudinal studies have identified a reduced risk for AD in patients (<70 yrs) previously treated with non-steroidal anti-inflammatory drugs for non-CNS afflictions that include arthritis. This review will focus on the interrelationships between the mechanisms of PS1, PS2 and betaAPP gene expression, tau and betaA deposition and the induction, regulation and proliferation in AD of the neuroinflammatory response. Novel therapeutic interventions in AD are discussed.

Aluminum↗

PubMedDate not supplied

Oxidative posttranslational modifications in Alzheimer disease. A possible pathogenic role in the formation of senile plaques and neurofibrillary tangles.

The distinctive pathological lesions of Alzheimer disease (AD), senile plaques, and neurofibrillary tangles comprise aggregates of insoluble fibrillar protein. We and other investigators recently demonstrated that several mechanisms related to oxidative stress and free-radical reactions could play a crucial role in the pathogenesis of AD and, specifically, in the formation of senile plaques and neurofibrillary tangles (NFT).

Alzheimer Disease↗

PubMed2006

Mapping the folding free energy surface for metal-free human Cu,Zn superoxide dismutase.

Mutations at many different sites in the gene encoding human Cu,Zn superoxide dismutase (SOD) are known to be causative agents in amyotrophic lateral sclerosis (ALS). One explanation for the molecular basis of this pathology is the aggregation of marginally soluble, partially structured states whose populations are enhanced in the protein variants. As a benchmark for testing this hypothesis, the equilibrium and kinetic properties of the reversible folding reaction of a metal-free variant of SOD were investigated. Reversibility was achieved by replacing the two non-essential cysteine residues with non-oxidizable analogs, C6A/C111S, to produce apo-AS-SOD. The metal-free pseudo-wild-type protein is folded and dimeric in the absence of chemical denaturants, and its equilibrium folding behavior is well described by an apparent two-state mechanism involving the unfolded monomer and the native dimer. The apparent free energy of folding in the absence of denaturant and at standard state is -20.37(+/- 1.04) kcal (mol dimer)(-1). A global analysis of circular dichroism kinetic traces for both unfolding and refolding reactions, combined with results from small angle X-ray scattering and time-resolved fluorescence anisotropy measurements, supports a sequential mechanism involving the unfolded monomer, a folded monomeric intermediate, and the native dimer. The rate-limiting monomer folding reaction is followed by a near diffusion-limited self-association reaction to form the native dimer. The relative population of the folded monomeric intermediate is predicted not to exceed 0.5% at micromolar concentrations of protein under equilibrium and both strongly unfolding and refolding conditions for metal-free pseudo-wild-type SOD.

Apoproteins↗

PubMed2002

Pro-inflammatory effects of aluminum in human glioblastoma cells.

Inflammatory events have been associated with senile plaques, one of the pathological hallmarks of Alzheimer's disease (AD). It is believed that aggregated beta-amyloid (betaA) proteins, which form the core of these plaques, may be responsible for triggering the inflammatory reaction. In the present study, the ability of aluminum (Al) to initiate similar inflammatory events was investigated in a human glioblastoma cell line. A 6-day exposure to either lipopolysaccharide (LPS) or aluminum sulfate caused a significant increase in the rate of proliferation of the glioblastoma cells. Both treatments also caused activation of the immune-responsive transcription factor NF-kappaB although there were time-related differences. The levels of secreted cytokines, interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) were both increased by the LPS treatment although exposure to Al decreased the secretion of the former while elevating the levels of the latter. These events may be due to the activation of glial cells and subsequent stress response to either Al complexes or LPS. Although exposure to either stress factor caused a stimulation of inflammatory markers, there were time-dependent differences in the response. This may reflect the ability of the cells to discern different stress factors and thus orchestrate an innate immune response profile distinct to each immunogen.

Alum Compounds↗

PubMed2002

Abnormal expression of cdk5 in focal cortical dysplasia in humans.

Focal cortical dysplasia (FCD) is an important cause of refractory epilepsy in humans. The origin of its pathognomonic abnormal cell types and the links between abnormal cell morphology and epileptogenicity remain unknown. The developmentally-regulated kinase cdk5 and its neuronal activator p35 are known to be central to a number of key components in neuronal development, cellular morphology, cytoskeletal function, synaptic plasticity and neurodegeneration. Here we examine eight cases of human FCD for expression of cdk5. We show abnormal cdk5 immunoreactivity and aggregation of protein suggesting alterations in cdk5 may also be involved in this important epileptogenic human pathology.

Cerebral Cortex↗