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Biomedical subjects

C L Masters

Publications and source records attributed to C L Masters.

At least 19 recordsLinked to original sources
PubMed2006

CSF BACE1 activity is increased in CJD and Alzheimer disease versus [corrected] other dementias.

To assess the diagnostic utility of CSF BACE1 activity for discriminating Alzheimer disease (AD) from other dementias, particularly Creutzfeldt-Jakob disease (CJD), the authors studied 26 patients with sporadic CJD, 21 patients with AD, and 21 patients with various non-AD, non-CJD dementias (DCs). CSF BACE1 activity was elevated in AD in comparison with DC (p = 0.01). Unexpectedly, CSF BACE1 activity was also increased in sporadic CJD (p = 0.02).

14-3-3 Proteins↗
PubMed2006

Determinants of diagnostic investigation sensitivities across the clinical spectrum of sporadic Creutzfeldt-Jakob disease.

To validate the provisional findings of a number of smaller studies and explore additional determinants of characteristic diagnostic investigation results across the entire clinical spectrum of sporadic Creutzfeldt-Jakob disease (CJD), an international collaborative study was undertaken comprising 2451 pathologically confirmed (definite) patients. We assessed the influence of age at disease onset, illness duration, prion protein gene (PRNP) codon 129 polymorphism (either methionine or valine) and molecular sub-type on the diagnostic sensitivity of EEG, cerebral MRI and the CSF 14-3-3 immunoassay. For EEG and CSF 14-3-3 protein detection, we also assessed the influence of the time point in a patient's illness at which the investigation was performed on the likelihood of a typical or positive result. Analysis included a large subset of patients (n = 743) in whom molecular sub-typing had been performed using a combination of the PRNP codon 129 polymorphism and the form of protease resistant prion protein [type 1 or 2 according to Parchi et al. (Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, Zerr I, Budka H, Kopp N, Piccardo P, Poser S, Rojiani A, Streichemberger N, Julien J, Vital C, Ghetti B, Gambetti P, Kretzschmar H. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999; 46: 224-233.)] present in the brain. Findings for the whole group paralleled the subset with molecular sub-typing data available, showing that age at disease onset and disease duration were independent determinants of typical changes on EEG, while illness duration significantly influenced positive CSF 14-3-3 protein detection; changes on brain MRI were not influenced by either of these clinical parameters, but overall, imaging data were less complete and consequently conclusions are more tentative. In addition to age at disease onset and illness duration, molecular sub-type was re-affirmed as an important independent determinant of investigation results. In multivariate analyses that included molecular sub-type, time point of the investigation during a patient's illness was found not to influence the occurrence of a typical or positive EEG or CSF 14-3-3 protein result. A typical EEG was most often seen in MM1 patients and was significantly less likely in the MV1, MV2 and VV2 sub-types, whereas VV2 patients had an increased likelihood of a typical brain MRI. Overall, the CSF 14-3-3 immunoassay was the most frequently positive investigation (88.1%) but performed significantly less well in the very uncommon MV2 and MM2 sub-types. Our findings confirm a number of determinants of principal investigation results in sporadic CJD and underscore the importance of recognizing these pre-test limitations before accepting the diagnosis excluded or confirmed. Combinations of investigations offer the best chance of detection, especially for the less common molecular sub-types such as MV2 and MM2.

14-3-3 Proteins↗
PubMed2005

Australian sporadic CJD analysis supports endogenous determinants of molecular-clinical profiles.

OBJECTIVE: To define the protease-resistant prion protein (PrPres) types and associated clinical profiles in Australian patients with sporadic Creutzfeldt-Jakob disease (CJD) to allow comparison with those reported from other continents and concomitantly reaffirm absence of variant CJD (vCJD). METHODS: Reassessment of available clinical and neuropathologic data on patients referred to the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR) who died between January 1, 1992, and June 30, 2003, was conducted. Molecular classification of PrPres was determined by immunoblot analysis of available frozen brain tissue. Brain homogenate pH and codon 129 genotype on the prion protein gene (PRNP) were established. RESULTS: PrPres patterns in 35 of 37 patients with sporadic CJD conformed to one of three common reported types. Of a range of clinical features assessed, illness duration was the only clinical feature significantly associated with PrPres type. Two patients displayed coexistence of more than one PrP type, with one displaying a novel pattern of three PrPres types in a single brain region. The absence of vCJD was reconfirmed, supported by the lack of the typical PrPres glycoform pattern. CONCLUSIONS: Given Australia's geographic isolation and environmental uniqueness, the general congruity of these results with those reported from other continents suggests that endogenous factors predominantly determine sporadic Creutzfeldt-Jakob disease (CJD) phenotypic subtypes or "strains." These results support a clinicopathologic classification system whereby both PrPres type and codon 129 genotype are utilized to most accurately depict phenotypic subtypes or strains of sporadic CJD.

Adult↗
PubMed2005

Imaginem oblivionis: the prospects of neuroimaging for early detection of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by the gradual onset of dementia. The pathological hallmarks of the disease are A beta amyloid plaques, neurofibrillary tangles, and reactive gliosis. Current diagnosis of AD is made by clinical, neuropsychologic, and neuroimaging assessments. Routine structural neuroimaging evaluation is based on non-specific features such as atrophy, a late feature in the progression of the disease, hence the crucial importance of developing new approaches for early and specific recognition at the prodromal stages of AD. Functional neuroimaging techniques such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) could prove to be valuable in the differential diagnosis of AD, as well as in assessing prognosis. With the advent of new therapeutic strategies aimed at reducing the A beta amyloid burden in the brain, there is increasing interest in the development of PET and SPECT radioligands that will permit the assessment of A beta amyloid burden in vivo. From this, the prospect of specific preclinical diagnosis arises, possibly in conjunction with other related A beta biomarkers in plasma and CSF.

Alzheimer Disease↗
PubMed2005

Rare genetically defined causes of dementia.

Several genetic disorders, though rare, are associated or present with dementia. Developments in the field of genetics are contributing to clarify and expand our knowledge of the complex physiopathological mechanisms leading to neurodegeneration and cognitive decline. Disorders associated with misfolded and aggregated proteins and lipid, metal or energy metabolism are examples of the multifarious disease processes converging in the clinical features of dementia, either as its predominant feature, as in cases of Alzheimer's disease (AD) or frontotemporal dementia (FTD), or as part of a cohort of accompanying or late-developing symptoms, as in Parkinson's disease (PD) or amyotrophic lateral sclerosis with dementia (ALS-D). Awareness of these disorders, allied with recent advances in genetic, biochemical and neuroimaging techniques, may lead to early diagnosis, successful treatment and better prognosis.

Amyotrophic Lateral Sclerosis↗
PubMed2005

Ethical considerations in presymptomatic testing for variant CJD.

Variant Creutzfeldt-Jakob disease (vCJD) is a fatal, transmissible, neurodegenerative disorder for which there is currently no effective treatment. vCJD arose from the zoonotic spread of bovine spongiform encephalopathy. There is now compelling evidence for human to human transmission through blood transfusions from presymptomatic carriers and experts are warning that the real epidemic may be yet to come. Imperatives exist for the development of reliable, non-invasive presymptomatic diagnostic tests. Research into such tests is well advanced. In this article the ethical implications of the availability of these tests are elaborated and comparisons drawn with predictive genetic testing for Huntington's disease and screening for HIV. Paramount to considerations is the issue of whom to test, weighing up respect for personal autonomy against obligations to benefit and protect society. A paradigm is proposed similar to that used for HIV screening but with unique features: compulsory testing of all blood/organ donors and individuals undergoing surgery or invasive procedures who have a significant risk of disease transmission.

Animals↗
PubMed2003

Novel prion protein insert mutation associated with prolonged neurodegenerative illness.

BACKGROUND: Mutations in the prion protein gene (PRNP) are found in approximately 13 to 15% of persons classified as dying from a transmissible spongiform encephalopathy. Point and octapeptide repeat insert and deletion mutations are described in the open reading frame (ORF) of PRNP. The authors present a clinicopathologic study of a patient with a family history of a lengthy and progressive neurodegenerative disorder associated with a novel large octapeptide repeat insert mutation. METHODS: Neuropathologic examination, including immunohistochemistry for the prion protein, was undertaken. The ORF of PRNP was amplified by PCR, cloned, and sequenced. Homogenate of cerebral tissue underwent Western blot analysis for the prion protein before and after proteinase K treatment. RESULTS: The proband died after a 16-year illness commencing at age 29 years. Confident premortem clinical diagnosis was not achieved despite a brain biopsy. Autopsy examination of the brain confirmed a spongiform encephalopathy. Prion protein immunohistochemistry revealed occasional granular deposits in the cerebellar granular layer. The proband was found to harbor a novel PRNP 168 base pair (bp) insert mutation. CONCLUSION: The authors have identified a novel 168 bp octapeptide repeat insert mutation. Prion protein immunohistochemistry differs from previous cases harboring seven octapeptide repeat and other long insert mutations. Optimization of PRNP analysis, especially PCR conditions, is essential to avoid overlooking this type of mutation and delay the correct molecular genetic diagnosis.

Adult↗
PubMed2003

Copper modulation of ion channels of PrP[106-126] mutant prion peptide fragments.

We have shown previously that the protease-resistant and neurotoxic prion peptide fragment PrP[106-126] of human PrP incorporates into lipid bilayer membranes to form heterogeneous ion channels, one of which is a Cu(2+)-sensitive fast cation channel. To investigate the role of PrP[106-126]'s hydrophobic core, AGAAAAGA, on its ability to form ion channels and their regulation with Cu(2+), we used the lipid-bilayer technique to examine membrane currents induced as a result of PrP[106-126] (AA/SS) and PrP[106-126] (VVAA/SSSS) interaction with lipid membranes and channel formation. Channel analysis of the mutant (VVAAA/SSS), which has a reduced hydrophobicity due to substitution of hydrophobic residues with the hydrophilic serine residue, showed a significant change in channel activity, which reflects a decrease in the beta-sheet structure, as shown by CD spectroscopy. One of the channels formed by the PrP[106-126] mutant has fast kinetics with three modes: burst, open and spike. The biophysical properties of this channel are similar to those of channels formed with other aggregation-prone amyloids, indicating their ability to form the common beta sheet-based channel structure. The current-voltage (I-V) relationship of the fast cation channel, which had a reversal potential, E(rev), between -40 and -10 mV, close to the equilibrium potential for K(+) ( E(K) = -35 mV), exhibited a sigmoidal shape. The value of the maximal slope conductance (g(max)) was 58 pS at positive potentials between 0 and 140 mV. Cu(2+) shifted the kinetics of the channel from being in the open and "burst" states to the spike mode. Cu(2+) reduced the probability of the channel being open (P(o)) and the mean open time (T(o)) and increased the channel's opening frequency (F(o)) and the mean closed time (T(c)) at a membrane potential ( V(m)) between +20 and + 140 mV. The fact that Cu(2+) induced changes in the kinetics of this channel with no changes in its conductance, indicates that Cu(2+) binds at the mouth of the channel via a fast channel block mechanism. The Cu(2+)-induced changes in the kinetic parameters of this channel suggest that the hydrophobic core is not a ligand Cu(2+) site, and they are in agreement with the suggestion that the Cu(2+)-binding site is located at M(109) and H(111) of this prion fragment. Although the data indicate that the hydrophobic core sequence plays a role in PrP[106-126] channel formation, it is not a binding site for Cu(2+). We suggest that the role of the hydrophobic region in modulating PrP toxicity is to influence PrP assembly into neurotoxic channel conformations. Such conformations may underlie toxicity observed in prion diseases. We further suggest that the conversions of the normal cellular isoform of prion protein (PrP(c)) to abnormal scrapie isoform (PrP(Sc)) and intermediates represent conversions to protease-resistant neurotoxic channel conformations.

Copper↗
PubMed2002

Creutzfeldt-Jakob disease in Australia 1970-1999.

OBJECTIVE: To ascertain all persons who developed a transmissible spongiform encephalopathy (TSE) within Australia during the 30-year period 1970 to 1999 through a comprehensive national surveillance program and subject the group to detailed epidemiologic analysis. METHODS: Cases were ascertained through reviews of morbidity separation coding data from all university-affiliated tertiary referral hospitals, as well as the centralized data bases of state and territory health departments, regular national death certificate searches, and semiannual mailout questionnaires to all neurologists and pathologists throughout Australia. Prospective monitoring commenced in September 1993. RESULTS: A total of 387 patients were confirmed as having TSE during this epoch. The majority of cases were sporadic Creutzfeldt-Jakob disease (CJD) (90.7%), with 7.2% heredofamilial and 2.1% iatrogenic. Over this 30-year period, the national average annual sporadic CJD incidence rate per million progressively increased from 0.31 for the decade 1970 through 1979 to 0.77 for 1980 through 1989, reaching 1.03 for 1990 through 1999. Death certificates were found to have a false-positive rate of 11.5% and sensitivity of 83.0% for sporadic CJD. CONCLUSIONS: Within Australia, there has been a gradual increase in the incidence of transmissible spongiform encephalopathy over the three-decade period 1970 through 1999, peaking in 1999 at 1.4/million/year for sporadic Creutzfeldt-Jakob disease. This increase is believed secondary to improved case ascertainment. Variant Creutzfeldt-Jakob disease was not identified during this period. Age- and sex-adjusted comparisons showed a decline in incidence rates in the elderly in both sexes, usually from age 74 years. Death certificates were a useful but imperfect method of case detection.

Adult↗
PubMed2002

Consensus neuropathological diagnosis of common dementia syndromes: testing and standardising the use of multiple diagnostic criteria.

The aim of this study was to assess the variation between neuropathologists in the diagnosis of common dementia syndromes when multiple published protocols are applied. Fourteen out of 18 Australian neuropathologists participated in diagnosing 20 cases (16 cases of dementia, 4 age-matched controls) using consensus diagnostic methods. Diagnostic criteria, clinical synopses and slides from multiple brain regions were sent to participants who were asked for case diagnoses. Diagnostic sensitivity, specificity, predictive value, accuracy and variability were determined using percentage agreement and kappa statistics. Using CERAD criteria, there was a high inter-rater agreement for cases with probable and definite Alzheimer's disease but low agreement for cases with possible Alzheimer's disease. Braak staging and the application of criteria for dementia with Lewy bodies also resulted in high inter-rater agreement. There was poor agreement for the diagnosis of frontotemporal dementia and for identifying small vessel disease. Participants rarely diagnosed more than one disease in any case. To improve efficiency when applying multiple diagnostic criteria, several simplifications were proposed and tested on 5 of the original 20 cases. Inter-rater reliability for the diagnosis of Alzheimer's disease and dementia with Lewy bodies significantly improved. Further development of simple and accurate methods to identify small vessel lesions and diagnose frontotemporal dementia is warranted.

Alzheimer Disease↗
PubMed2002

Generation of a recombinant Fab antibody reactive with the Alzheimer's disease-related Abeta peptide.

A recombinant Fab antibody, designated 1E8-4b, which reacts with the Alzheimer's disease (AD)-related Abeta peptides, Abeta[1-40], Abeta[1-42] and Abeta[1-43] has been developed. The 1E8-4b Fab was constructed by cloning the V(H)C(H1) and V(L)C(L) domains from the parent hybridoma 1E8 antibody, reported previously to recognize these Abeta peptides. Briefly, a C-terminal Flag tag sequence was incorporated into this construct, which was ligated into the vector pHFA2 and expressed in Escherichia coli. Following purification on an M2 anti-Flag affinity column, the 1E8-4b recombinant Fab antibody was shown to bind plaques within sections of brain tissue from CERAD-defined AD patients by immunohistochemistry. ELISA, epitope mapping and immunoblotting confirmed the recognition of the Abeta1-40/42/43] peptides by the 1E8-4b Fab. The 1E8-4b Fab did not recognize APP695 or APP770 which contain the Abeta sequence. The Abeta specificity of the recombinant 1E8-4b Fab antibody was identical to the parent 1E8 monoclonal antibody.

Alzheimer Disease↗
PubMed2001

Pharmacological knock-down of the presenilin 1 heterodimer by a novel gamma -secretase inhibitor: implications for presenilin biology.

Intramembranous cleavage of the beta-amyloid precursor protein by gamma-secretase is the final processing event generating amyloid-beta peptides, which are thought to be causative agents for Alzheimer's disease. Missense mutations in the presenilin genes co-segregate with early-onset Alzheimer's disease, and, recently, a close biochemical linkage between presenilins and the identity of gamma-secretase has been established. Here we describe for the first time that certain potent gamma-secretase inhibitors are able to interfere with the endoproteolytic processing of presenilin 1 (PS1). In addition, we identified a novel gamma-secretase inhibitor, [1S-benzyl-4R-[1-(5-cyclohexyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3(R,S)-ylcarbamoyl)-S-ethylcarbamoyl]-2R-hydroxy-5-phenyl-pentyl]-carbamic acid tert-butyl ester (CBAP), which not only physically interacts with PS1, but upon chronic treatment produces a "pharmacological knock-down" of PS1 fragments. This indicates that the observed accumulation of full-length PS1 is caused by a direct inhibition of its endoproteolysis. The subsequent use of CBAP as a biological tool to increase full-length PS1 levels in the absence of exogenous PS1 expression has provided evidence that wild-type PS1 endoproteolysis is not required either for PS1/gamma-secretase complex assembly or trafficking. Furthermore, in cell-based systems CBAP does not completely recapitulate PS1 loss-of-function phenotypes. Even though the beta-amyloid precursor protein cleavage and the S3 cleavage of the Notch receptor are inhibited by CBAP, an impairment of Trk receptor maturation was not observed.

Amyloid Precursor Protein Secretases↗
PubMed2001

Involvement of the 5-lipoxygenase pathway in the neurotoxicity of the prion peptide PrP106-126.

Transmissible spongiform encephalopathies are characterised by the transformation of the normal cellular prion protein (PrP(C)) into an abnormal isoform (PrP(TSE)). Previous studies have shown that N-methyl-D-aspartate (NMDA) receptor antagonists can inhibit glutathione depletion and neurotoxicity induced by PrP(TSE) and a toxic prion protein peptide, PrP106-126, in vitro. NMDA receptor activation is known to increase intracellular accumulation of Ca(2+), resulting in up-regulation of arachidonic acid (AA) metabolism. This can stimulate the lipoxygenase pathways that may generate a number of potentially neurotoxic metabolites. Because of the putative relationship between AA breakdown and PrP106-126 neurotoxicity, we investigated AA metabolism in primary cerebellar granule neuron cultures treated with PrP106-126. Our studies revealed that PrP106-126 exposure for 30 min significantly up-regulated AA release from cerebellar granule neurons. PrP106-126 neurotoxicity was mediated through the 5-lipoxygenase (5-LOX) pathway, as shown by abrogation of neuronal death with the 5-LOX inhibitors quinacrine, nordihydroguaiaretic acid, and caffeic acid. These inhibitors also prevented PrP106-126-induced caspase 3 activation and annexin V binding, indicating a central role for the 5-LOX pathway in PrP106-126-mediated proapoptosis. Interestingly, inhibitors of the 12-lipoxygenase pathway had no effect on PrP106-126 neurotoxicity or proapoptosis. These studies clearly demonstrate that AA metabolism through the 5-LOX pathway is an important early event in PrP106-126 neurotoxicity and consequently may have a critical role in PrP(TSE)-mediated cell loss in vivo. If this is so, therapeutic intervention with 5-LOX inhibitors may prove beneficial in the treatment of prion disorders.

Animals↗
PubMed2001

Aspartyl protease inhibitor pepstatin binds to the presenilins of Alzheimer's disease.

Mutations in the presenilin genes PS1 and PS2 cause early-onset Alzheimer's disease by altering gamma-secretase cleavage of the amyloid precursor protein, the last step in the generation of Abeta peptide. Ablation of presenilin (PS) genes, or mutation of two critical aspartates, abolishes gamma-secretase cleavage, suggesting that PS may be the gamma-secretases. Independently, inhibition experiments indicate that gamma-secretase is an aspartyl protease. To characterize the putative gamma-secretase activity associated with presenilins, lysates from human neuroblastoma SH-SY5Y and human brain homogenates were incubated with biotin derivatives of pepstatin, followed by immunoprecipitation of PS and associated proteins, and biotin detection by Western blotting. Precipitation with PS1 antibodies, directed to either N-terminal or loop regions, yielded the same 43 kDa band, of apparent molecular mass consistent with that of full-length PS1, although it may represent an aspartyl protease complexed with PS1. Incubation of cell lysates with pepstatin-biotin, followed by streptavidin precipitation and PS1 Western blotting, revealed PS1 fragments and full-length protein, indicating that pepstatin-biotin bound to both cleaved and uncleaved PS1. Binding could be competed by gamma-secretase inhibitor L-685,458 and could not be achieved with a PS1 mutant lacking the two transmembrane aspartates. Pepstatin-biotin was also shown to bind to PS2. PS1 was specifically absorbed to pepstatin-agarose, with an optimal pH of 6. Binding of pepstatin-biotin to PS1 from lymphocytes of a heterozygous carrier of pathologic exon 9 deletion was markedly decreased as compared to control lymphocytes, suggesting that this PS1 mutation altered the pepstatin binding site.

Alzheimer Disease↗
PubMed2001

Copper and zinc binding modulates the aggregation and neurotoxic properties of the prion peptide PrP106-126.

The abnormal form of the prion protein (PrP) is believed to be responsible for the transmissible spongiform encephalopathies. A peptide encompassing residues 106-126 of human PrP (PrP106-126) is neurotoxic in vitro due its adoption of an amyloidogenic fibril structure. The Alzheimer's disease amyloid beta peptide (Abeta) also undergoes fibrillogenesis to become neurotoxic. Abeta aggregation and toxicity is highly sensitive to copper, zinc, or iron ions. We show that PrP106-126 aggregation, as assessed by turbidometry, is abolished in Chelex-100-treated buffer. ICP-MS analysis showed that the Chelex-100 treatment had reduced Cu(2+) and Zn(2+) levels approximately 3-fold. Restoring Cu(2+) and Zn(2+) to their original levels restored aggregation. Circular dichroism showed that the Chelex-100 treatment reduced the aggregated beta-sheet content of the peptide. Electron paramagnetic resonance spectroscopy identified a 2N1S1O coordination to the Cu(2+) atom, suggesting histidine 111 and methionine 109 or 112 are involved. Nuclear magnetic resonance confirmed Cu(2+) and Zn(2+) binding to His-111 and weaker binding to Met-112. An N-terminally acetylated PrP106-126 peptide did not bind Cu(2+), implicating the free amino group in metal binding. Mutagenesis of either His-111, Met-109, or Met-112 abolished PrP106-126 neurotoxicity and its ability to form fibrils. Therefore, Cu(2+) and/or Zn(2+) binding is critical for PrP106-126 aggregation and neurotoxicity.

Amino Acid Sequence↗
PubMed2001

Memory decline in healthy older people: implications for identifying mild cognitive impairment.

BACKGROUND: Criteria for mild cognitive impairment require objective evidence of a memory deficit but do not require objective evidence of memory decline. Application of these criteria may therefore result in the misclassification of older patients with memory decline as normal because their neuropsychological test performance at a single point in time may be within normal limits. This study aimed to identify and characterize older people with memory decline. METHOD: Word list delayed recall (WLDR) test performance was assessed on five occasions during a 2-year period in a cohort of healthy older individuals. Older people with declining (n = 35) and nondeclining (n = 66) WLDR scores were identified. Both subgroups were then compared on apoE genotype, Clinical Dementia Rating, and neuropsychological test performance at the fifth assessment. RESULTS: Thirty-four percent of the group with declining memory recorded a Clinical Dementia Rating of 0.5, compared with 5% of the nondeclining memory group. No between-group differences were observed in cognitive domains other than memory, self-reported cognitive failures, or the proportion of each group carrying the apoE epsilon 4 allele. CONCLUSIONS: A large proportion of healthy older individuals show memory decline, which may represent the early stages of a potentially more severe cognitive impairment. Further investigation is necessary to determine the relationship between apoE genotype, self-reported cognitive impairment, and memory decline in older people.

Aged↗
PubMed2001

Alzheimer's disease amyloid-beta binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits.

Amyloid beta peptide (Abeta) is the major constituent of extracellular plaques and perivascular amyloid deposits, the pathognomonic neuropathological lesions of Alzheimer's disease. Cu(2+) and Zn(2+) bind Abeta, inducing aggregation and giving rise to reactive oxygen species. These reactions may play a deleterious role in the disease state, because high concentrations of iron, copper, and zinc have been located in amyloid in diseased brains. Here we show that coordination of metal ions to Abeta is the same in both aqueous solution and lipid environments, with His(6), His(13), and His(14) all involved. At Cu(2+)/peptide molar ratios >0.3, Abeta coordinated a second Cu(2+) atom in a highly cooperative manner. This effect was abolished if the histidine residues were methylated at N(epsilon)2, indicating the presence of bridging histidine residues, as found in the active site of superoxide dismutase. Addition of Cu(2+) or Zn(2+) to Abeta in a negatively charged lipid environment caused a conformational change from beta-sheet to alpha-helix, accompanied by peptide oligomerization and membrane penetration. These results suggest that metal binding to Abeta generated an allosterically ordered membrane-penetrating oligomer linked by superoxide dismutase-like bridging histidine residues.

Allosteric Regulation↗