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The 68K protease has beta-secretase-like activity for lymphocyte precursor protein but not for brain substrate.

https://arctichealth.org/en/permalink/ahliterature199515
Source
Neuroreport. 2000 Feb 7;11(2):373-7
Publication Type
Article
Date
Feb-7-2000
Author
A. Matsumoto
Author Affiliation
Department of Radiation Biophysics and Genetics, Kobe University School of Medicine, Japan.
Source
Neuroreport. 2000 Feb 7;11(2):373-7
Date
Feb-7-2000
Language
English
Publication Type
Article
Keywords
Aged
Aged, 80 and over
Alzheimer Disease - enzymology
Amino Acid Sequence
Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor - metabolism
Aspartic Acid Endopeptidases - metabolism
Blotting, Western
Cells, Cultured
Cerebral Cortex - enzymology
Chondroitin ABC Lyase - metabolism
Endopeptidases
Female
Humans
Isoenzymes - metabolism
Lymphocytes - cytology - enzymology
Male
Middle Aged
Molecular Sequence Data
Organ Specificity
Peptide Fragments - chemistry
Polysaccharide-Lyases - metabolism
Protein Processing, Post-Translational
Sequence Analysis, Protein
Serine Endopeptidases - metabolism
Substrate Specificity
Abstract
Processing and metabolism of beta-amyloid precursor protein (APP) and generation of a variety of beta-amyloid (Abeta) peptides in the human brain is essentially associated with pathophysiology of Alzheimer's disease (AD). APP degradation activity of the 68 kDa serine protease, which was originally prepared from familial AD lymphoblastoid cells and harbors beta-secretase-like activity, was analyzed by Western blot using anti Abeta 1/40 antibody and anti APP cytoplasmic domain (CT) antibody. Native lymphocyte APP (LAPP) prepared from normal or AD-derived lymphoblastoid cells was degraded by the protease, generating a 16 kDa Abeta-bearing C-terminal fragment of APP. N-terminal amino acid sequencing of the fragment indicated that the protease cleaves LAPP at the Abeta-N-terminus. When the LAPP was treated with chondroitinase ABC prior to proteolysis, the activity to generate the fragment was inhibited, but pretreatment with heparitinase resulted in no effect. Native hippocampal APP prepared from normal brain, however, did not generate the 16 kDa peptide by the protease treatment. These results suggest that the process of APP degradation and Abeta-peptides generation, including beta-secretase activity, is associated with tissue specificity of both APP substrate and proteases. They also indicate that sulfated glycoconjugates attached to a portion of APP isoforms may play a role as a molecular determinant in the proteolysis.
PubMed ID
10674489 View in PubMed
Less detail

Abeta oligomer-mediated long-term potentiation impairment involves protein phosphatase 1-dependent mechanisms.

https://arctichealth.org/en/permalink/ahliterature162439
Source
J Neurosci. 2007 Jul 18;27(29):7648-53
Publication Type
Article
Date
Jul-18-2007
Author
Marlen Knobloch
Mélissa Farinelli
Uwe Konietzko
Roger M Nitsch
Isabelle M Mansuy
Author Affiliation
Division of Psychiatry Research, University of Zurich, 8008 Zurich, Switzerland.
Source
J Neurosci. 2007 Jul 18;27(29):7648-53
Date
Jul-18-2007
Language
English
Publication Type
Article
Keywords
Age Factors
Amyloid Precursor Protein Secretases - genetics
Amyloid beta-Peptides - chemistry - metabolism - ultrastructure
Analysis of Variance
Animals
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium-Calmodulin-Dependent Protein Kinases - genetics
Dose-Response Relationship, Radiation
Electric Stimulation - methods
Excitatory Postsynaptic Potentials - drug effects - physiology
Gene Expression Regulation - genetics
Hippocampus - cytology
Humans
Long-Term Potentiation - genetics - physiology - radiation effects
Mice
Mice, Transgenic
Microscopy, Electron, Transmission - methods
Neurons - drug effects - physiology
Patch-Clamp Techniques
Phosphoprotein Phosphatases - physiology
Presenilin-1 - genetics
Protein Phosphatase 1
Reverse Transcriptase Polymerase Chain Reaction - methods
Abstract
Amyloid beta (Abeta) oligomers are derived from proteolytic cleavage of amyloid precursor protein (APP) and can impair memory and hippocampal long-term potentiation (LTP) in vivo and in vitro. They are recognized as the primary neurotoxic agents in Alzheimer's disease. The mechanisms underlying such toxicity on synaptic functions are complex and not fully understood. Here, we provide the first evidence that these mechanisms involve protein phosphatase 1 (PP1). Using a novel transgenic mouse model expressing human APP with the Swedish and Arctic mutations that render Abeta more prone to form oligomers (arcAbeta mice), we show that the LTP impairment induced by Abeta oligomers can be fully reversed by PP1 inhibition in vitro. We further demonstrate that the genetic inhibition of endogenous PP1 in vivo confers resistance to Abeta oligomer-mediated toxicity and preserves LTP. Overall, these results reveal that PP1 is a key player in the mechanisms of AD pathology.
PubMed ID
17634359 View in PubMed
Less detail

The Arctic Alzheimer mutation favors intracellular amyloid-beta production by making amyloid precursor protein less available to alpha-secretase.

https://arctichealth.org/en/permalink/ahliterature78004
Source
J Neurochem. 2007 May;101(3):854-62
Publication Type
Article
Date
May-2007
Author
Sahlin Charlotte
Lord Anna
Magnusson Kristina
Englund Hillevi
Almeida Claudia G
Greengard Paul
Nyberg Fred
Gouras Gunnar K
Lannfelt Lars
Nilsson Lars N G
Author Affiliation
Department of Public Health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden. charlotte.sahlin@pubcare.uu.se
Source
J Neurochem. 2007 May;101(3):854-62
Date
May-2007
Language
English
Publication Type
Article
Keywords
Amyloid Precursor Protein Secretases - metabolism
Amyloid beta-Protein - genetics
Cell Line, Tumor
Humans
Mutagenesis, Site-Directed - methods
Mutation - physiology
Neuroblastoma
Protein Structure, Tertiary
Transfection - methods
Abstract
Mutations within the amyloid-beta (Abeta) domain of the amyloid precursor protein (APP) typically generate hemorrhagic strokes and vascular amyloid angiopathy. In contrast, the Arctic mutation (APP E693G) results in Alzheimer's disease. Little is known about the pathologic mechanisms that result from the Arctic mutation, although increased formation of Abeta protofibrils in vitro and intraneuronal Abeta aggregates in vivo suggest that early steps in the amyloidogenic pathway are facilitated. Here we show that the Arctic mutation favors proamyloidogenic APP processing by increased beta-secretase cleavage, as demonstrated by altered levels of N- and C-terminal APP fragments. Although the Arctic mutation is located close to the alpha-secretase site, APP harboring the Arctic mutation is not an inferior substrate to a disintegrin and metalloprotease-10, a major alpha-secretase. Instead, the localization of Arctic APP is altered, with reduced levels at the cell surface making Arctic APP less available for alpha-secretase cleavage. As a result, the extent and subcellular location of Abeta formation is changed, as revealed by increased Abeta levels, especially at intracellular locations. Our findings suggest that the unique clinical symptomatology and neuropathology associated with the Arctic mutation, but not with other intra-Abeta mutations, could relate to altered APP processing with increased steady-state levels of Arctic Abeta, particularly at intracellular locations.
PubMed ID
17448150 View in PubMed
Less detail

Correlation between HIV-1 seropositivity and prevalence of a gamma-secretase polymorphism in two distinct ethnic populations.

https://arctichealth.org/en/permalink/ahliterature148387
Source
J Med Virol. 2009 Nov;81(11):1847-51
Publication Type
Article
Date
Nov-2009
Author
Karen M J van Loo
Jessica E van Schijndel
Martine van Zweeden
Daniëlle van Manen
Mieke D Trip
Desiree C Petersen
Hanneke Schuitemaker
Vanessa M Hayes
Gerard J M Martens
Author Affiliation
Department of Molecular Animal Physiology, Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour and Nijmegen Center for Molecular Life Sciences, Nijmegen 6525 GA , The Netherlands.
Source
J Med Virol. 2009 Nov;81(11):1847-51
Date
Nov-2009
Language
English
Publication Type
Article
Keywords
Amino Acid Substitution - genetics
Amyloid Precursor Protein Secretases - genetics
Disease Susceptibility
Female
HIV Infections - genetics
Humans
Male
Membrane Proteins - genetics
Mutation, Missense
Peptide Hydrolases - genetics
Polymorphism, Single Nucleotide
Abstract
Susceptibility for human immunodeficiency virus type 1 (HIV-1) infection may be influenced by host genetics. Recent findings with a Wistar rat model raised the possibility that the gamma-secretase pathway may be associated with an individual's susceptibility to infection. A functional single-nucleotide polymorphism (SNP) in the gamma-secretase component APH1B (Phe217Leu; rs1047552) was therefore analyzed for association with HIV-1 infection. The SNP showed a tendency for association with HIV-1 infection in a Xhosa indigenous South African Bantu study (P = 0.087), and associated significantly in a Caucasian Dutch study (P = 0.049). Together, the results suggest a role for the gamma-secretase pathway in susceptibility to HIV-1 infection.
PubMed ID
19774691 View in PubMed
Less detail

Decreased alpha-secretase-cleaved amyloid precursor protein as a diagnostic marker for Alzheimer's disease.

https://arctichealth.org/en/permalink/ahliterature214662
Source
Nat Med. 1995 Aug;1(8):829-32
Publication Type
Article
Date
Aug-1995
Author
L. Lannfelt
H. Basun
L O Wahlund
B A Rowe
S L Wagner
Author Affiliation
Karolinska Institute, Department of Clinical Neuroscience (Geriatric Medicine), Huddinge University Hospital, Sweden.
Source
Nat Med. 1995 Aug;1(8):829-32
Date
Aug-1995
Language
English
Publication Type
Article
Keywords
Adult
Aged
Alzheimer Disease - cerebrospinal fluid - diagnosis - genetics
Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor - immunology - metabolism
Aspartic Acid Endopeptidases
Biological Markers - cerebrospinal fluid
Blotting, Western
Endopeptidases - metabolism
Enzyme-Linked Immunosorbent Assay - methods
Heterozygote
Humans
Middle Aged
Mutation
Peptide Fragments - immunology - metabolism
Sweden - epidemiology
Abstract
The neuropathologic hallmarks of Alzheimer's disease (AD) are extracellular plaques and intracellular neurofibrillary tangles. A constituent of senile plaques in AD is beta-amyloid, a hydrophobic peptide of 39-43 amino acids and a fragment of the amyloid precursor protein (APP). APP can be metabolized by at least two pathways, one of which involves generation of soluble APP by an unidentified enzyme named alpha-secretase. This cleavage generates alpha-secretase-cleaved, soluble APP (alpha-sAPP), which in this investigation was measured by a new assay in cerebrospinal fluid (CSF) from members of a Swedish AD family with a pathogenic mutation at APP670/671 (ref. 2). Family members who carry the mutation and are diagnosed with AD had low levels of alpha-sAPP (160 +/- 48 ng ml-1), with no overlap compared with non-carriers (257 +/- 48 ng ml-1). Carriers of the presymptomatic mutation showed intermediate alpha-sAPP levels. Today there exists no antemortem marker in AD with sufficient sensitivity and specificity, but measurement of alpha-sAPP represents a new and promising diagnostic marker.
PubMed ID
7585189 View in PubMed
Less detail

Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II trial.

https://arctichealth.org/en/permalink/ahliterature157435
Source
Lancet Neurol. 2008 Jun;7(6):483-93
Publication Type
Article
Date
Jun-2008
Author
Gordon K Wilcock
Sandra E Black
Suzanne B Hendrix
Kenton H Zavitz
Edward A Swabb
Mark A Laughlin
Author Affiliation
University of Oxford, John Radcliffe Hospital, Oxford, UK. gordon.wilcock@ndm.ox.ac.uk
Source
Lancet Neurol. 2008 Jun;7(6):483-93
Date
Jun-2008
Language
English
Publication Type
Article
Keywords
Aged
Aged, 80 and over
Alzheimer Disease - drug therapy - metabolism - physiopathology
Amyloid Precursor Protein Secretases - antagonists & inhibitors - metabolism
Amyloid beta-Peptides - antagonists & inhibitors - metabolism
Anti-Inflammatory Agents, Non-Steroidal - administration & dosage - adverse effects
Brain - drug effects - metabolism - physiopathology
Canada
Diarrhea - chemically induced
Disease Progression
Dose-Response Relationship, Drug
Drug Administration Schedule
Enzyme Inhibitors - administration & dosage - adverse effects
Female
Flurbiprofen - administration & dosage - adverse effects
Great Britain
Humans
Male
Middle Aged
Nausea - chemically induced
Placebo Effect
Treatment Outcome
Abstract
The amyloid-beta peptide Abeta(42) has been implicated in the pathogenesis of Alzheimer's disease (AD). We aimed to test the effects of tarenflurbil, a selective Abeta(42)-lowering agent (SALA), on cognition and function in patients with mild to moderate AD.
210 patients living in the community who had a mini-mental state examination (MMSE) score of 15-26 were randomly assigned to receive tarenflurbil twice per day (400 mg [n=69] or 800 mg [n=70]) or placebo (n=71) for 12 months in a phase II, multicentre, double-blind study. Primary efficacy outcomes were the AD assessment scale cognitive subscale (ADAS-cog), the Alzheimer's Disease Cooperative Study activities of daily living scale (ADCS-ADL), and the clinical dementia rating sum of boxes (CDR-sb). In a 12-month extended treatment phase, patients who had received tarenflurbil continued to receive the same dose, and patients who had received placebo were randomly assigned to tarenflurbil at 800 mg or 400 mg twice per day. Primary efficacy analyses were done by intention to treat. This trial is registered with Health Canada (084527) and the Medicines and Healthcare products Regulatory Agency in the UK (20365/0001/A 69316).
A prespecified interaction analysis revealed that patients with mild AD (baseline MMSE 20-26) and moderate AD (baseline MMSE 15-19) responded differently to tarenflurbil in the ADAS-cog and the ADCS-ADL (p>or=0.10); therefore, these groups were analysed separately. Patients with mild AD in the 800 mg tarenflurbil group had lower rates of decline than did those in the placebo group in activities of daily living (ADCS-ADL difference in slope 3.98 [95% CI 0.33 to 7.62] points per year, effect size [reduction from placebo decline rate] 46.4%, Cohen's d 0.45; p=0.033) and global function (CDR-sb difference -0.80 [-1.57 to -0.03] points per year, effect size 35.7%, Cohen's d 0.42; p=0.042); slowing of cognitive decline did not differ significantly (ADAS-cog difference -1.36 [-4.07 to 1.36] points per year, effect size 33.7%, Cohen's d 0.20; p=0.327). In patients with moderate AD, 800 mg tarenflurbil twice per day had no significant effects on ADCS-ADL and ADAS-cog and had a negative effect on CDR-sb (-52%, Cohen's d -1.08; p=0.003). The most common adverse events were diarrhoea (in seven, nine, and five patients in the 800 mg, 400 mg, and placebo groups, respectively), nausea (in seven, seven, and four patients), and dizziness (in five, nine, and four patients). Patients with mild AD who were in the 800 mg tarenflurbil group for 24 months had lower rates of decline for all three primary outcomes than did patients who were in the placebo group for months 0-12 and a tarenflurbil group for months 12-24 (all p
Notes
Comment In: Lancet Neurol. 2008 Jun;7(6):468-918450518
Erratum In: Lancet Neurol. 2008 Jul;7(7):575
Erratum In: Lancet Neurol. 2011 Apr;10(4):297
PubMed ID
18450517 View in PubMed
Less detail

Identification of beta-secretase-like activity using a mass spectrometry-based assay system.

https://arctichealth.org/en/permalink/ahliterature199767
Source
Nat Biotechnol. 2000 Jan;18(1):66-70
Publication Type
Article
Date
Jan-2000
Author
F. Grüninger-Leitch
P. Berndt
H. Langen
P. Nelboeck
H. Döbeli
Author Affiliation
CNS Research, Hoffmann-La Roche Ltd, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
Source
Nat Biotechnol. 2000 Jan;18(1):66-70
Date
Jan-2000
Language
English
Publication Type
Article
Keywords
Amino Acid Sequence
Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor - genetics - metabolism
Animals
Aspartic Acid Endopeptidases - chemistry - metabolism
Cathepsin D - chemistry - metabolism
Cathepsin E - genetics - metabolism
Cell Extracts - chemistry
Cell Line
Ceramics
Endopeptidases
Humans
Metalloendopeptidases - metabolism
Mice
Microspheres
Molecular Sequence Data
Molecular Weight
Mutation - genetics
Pepstatins - metabolism
Peptide Fragments - chemistry - metabolism
Rats
Recombinant Fusion Proteins - chemistry - metabolism
Reproducibility of Results
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization - methods
Substrate Specificity
Sweden
Transfection
Abstract
We describe an assay system for the identification of site-specific proteases. The assay is based on a protein substrate that is immobilized on ceramic beads. After incubation with cell homogenates, the beads are washed and digested with endoproteinase Lys-C to liberate a defined set of peptides. The peptide fragments are identified by mass spectrometry. The assay was used to screen for beta-secretase, the protease that cleaves amyloid precursor protein (APP) at the beta-site. Cathepsin D was identified as the enzyme responsible for beta-secretase-like activity in two cell lines. Subsequent analysis of the related aspartic protease, cathepsin E, revealed almost identical cleavage specificity. Both enzymes are efficient in cleaving Swedish mutant APP at the beta-site but show almost no reactivity with wild-type APP. Treatment of cell lines with pepstatin inhibited the production of amyloid peptide (Abeta) when they were transfected with a construct bearing the Swedish APP mutant. However, when the cells were transfected with wild-type APP, the generation of Abeta was increased. This suggests that more than one enzyme is capable of generating Abeta in vivo and that an aspartic protease is involved in the processing of Swedish mutant APP.
PubMed ID
10625394 View in PubMed
Less detail

Measurement of alpha- and beta-secretase cleaved amyloid precursor protein in cerebrospinal fluid from Alzheimer patients.

https://arctichealth.org/en/permalink/ahliterature183795
Source
Exp Neurol. 2003 Sep;183(1):74-80
Publication Type
Article
Date
Sep-2003
Author
Annika Olsson
Kina Höglund
Magnus Sjögren
Niels Andreasen
Lennart Minthon
Lars Lannfelt
Katharina Buerger
Hans Jürgen Möller
Harald Hampel
Pia Davidsson
Kaj Blennow
Author Affiliation
Institute of Clinical Neuroscience, Experimental Neuroscience Section, Göteborg University, Sahlgrenska University Hospital/, Mölndal, Sweden. Annika.Olsson@neuro.gu.se
Source
Exp Neurol. 2003 Sep;183(1):74-80
Date
Sep-2003
Language
English
Publication Type
Article
Keywords
Aged
Alleles
Alzheimer Disease - cerebrospinal fluid - genetics
Amyloid Precursor Protein Secretases
Amyloid beta-Peptides - cerebrospinal fluid
Amyloid beta-Protein Precursor - cerebrospinal fluid - metabolism
Apolipoproteins E - genetics
Aspartic Acid Endopeptidases - metabolism
Blotting, Western
Endopeptidases - metabolism
Enzyme-Linked Immunosorbent Assay - methods
Germany
Humans
Middle Aged
Peptide Fragments - cerebrospinal fluid
Reference Values
Reproducibility of Results
Sensitivity and specificity
Sweden
Abstract
One of the major histopathological hallmarks of Alzheimer's disease (AD) is redundant senile plaques mainly composed of beta-amyloid (Abeta) aggregates. Alternative cleavage of the amyloid precursor protein (APP), occurring in both normal and AD subjects, results in the generation and secretion of soluble APP (sAPP) and Abeta. We examined the cerebrospinal fluid (CSF) for alpha- and beta-secretase cleaved sAPP (alpha-sAPP and beta-sAPP) in 81 sporadic AD patients, 19 patients with mild cognitive impairment, and 42 healthy controls by using newly developed sandwich enzyme-linked immunosorbent assay methods. We found that neither the level of CSF-alpha-sAPP nor CSF-beta-sAPP differed between sporadic AD patients and healthy controls. These findings further support the conclusion that there is no change in APP expression in sporadic AD. However, the level of CSF-beta-sAPP was significantly increased in patients with mild cognitive impairment compared to controls. We also investigated the relationship between the CSF level of alpha/beta-sAPP and Abeta(42) and the apoE epsilon 4 (apoE4) allele. Significantly lower levels of CSF-alpha-sAPP were found in AD patients possessing one or two apoE4 alleles than in those not possessing the apoE4 allele. Neither the levels of CSF-beta-sAPP nor CSF-Abeta(42) differed when comparing ApoE4 allele-positive with allele-negative individuals.
Notes
Comment In: Exp Neurol. 2003 Sep;183(1):7-1012957483
PubMed ID
12957490 View in PubMed
Less detail

Platelet alpha- and beta- secretase activities are not significantly affected by dementia or mild cognitive impairment in Swedish patients.

https://arctichealth.org/en/permalink/ahliterature148844
Source
Curr Alzheimer Res. 2010 Mar;7(2):134-9
Publication Type
Article
Date
Mar-2010
Author
P. Gorham
N. Bark
I. Björkhem
S. Meaney
M. Crisby
Author Affiliation
Department of Neurobiology, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden.
Source
Curr Alzheimer Res. 2010 Mar;7(2):134-9
Date
Mar-2010
Language
English
Publication Type
Article
Keywords
Aged
Alzheimer Disease - enzymology - physiopathology - psychology
Amyloid Precursor Protein Secretases - analysis - metabolism
Amyloid beta-Protein Precursor - metabolism
Biological Markers - analysis - metabolism
Blood Platelets - enzymology
Cell Membrane - metabolism
Cognition Disorders - enzymology - pathology - physiopathology
Cohort Studies
Enzyme Assays - methods
Humans
Membrane Lipids - analysis - metabolism
Sweden
Triglycerides - analysis - blood
Abstract
The processing of the Amyloid Precursor Protein (APP) is a critical event in the formation of amyloid plaques which are composed of the 4kDa amyloid beta-peptide (Abeta). Processing of APP occurs through a non-amyloidogenic pathway, mediated by initial alpha-secretase cleavage or through an amyloidogenic pathway via sequential cleavage by beta- and gamma-secretase enzymes, which produces Abeta peptides. Currently, the diagnosis of probable or possible Alzheimer's disease (AD) is primarily based on neuropsychological and neuroradiological assessment. Recent reports indicate that platelet beta-secretase activity is moderately increased in patients with AD and mild cognitive impairment (MCI). To our knowledge platelet alpha-secretase activity has not yet been explored in this context and estimation of the ratio of the activities of alpha- and beta-secretase in platelets may represent a useful surrogate marker of the balance between the two pathways of APP metabolism and be of importance for the diagnosis of AD. We therefore considered it of interest to develop assays of platelet alpha- and beta-secretase activities suitable for such clinical investigations. Application of these assays to a Swedish population failed to uncover an effect of AD or MCI on individual platelet secretase activities or the secretase ratio. However, we did observe an inverse correlation between plasma triacylglycerol levels and the secretase ratio. The results are discussed in the context of the clinical usefulness of the secretase ratio as a biochemical adjunct to the diagnosis of AD.
PubMed ID
19715551 View in PubMed
Less detail

Point mutations in Aß result in the formation of distinct polymorphic aggregates in the presence of lipid bilayers.

https://arctichealth.org/en/permalink/ahliterature137607
Source
PLoS One. 2011;6(1):e16248
Publication Type
Article
Date
2011
Author
Phillip M Pifer
Elizabeth A Yates
Justin Legleiter
Author Affiliation
The C Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, West Virginia, United States of America.
Source
PLoS One. 2011;6(1):e16248
Date
2011
Language
English
Publication Type
Article
Keywords
Amyloid Precursor Protein Secretases - metabolism
Amyloid beta-Peptides - chemistry - genetics - metabolism
Genetic Predisposition to Disease
Humans
Hydrophobic and Hydrophilic Interactions
Lipid Bilayers - metabolism
Membrane Lipids - metabolism
Point Mutation
Protein Multimerization - genetics
Abstract
A hallmark of Alzheimer's disease (AD) is the rearrangement of the ß-amyloid (Aß) peptide to a non-native conformation that promotes the formation of toxic, nanoscale aggregates. Recent studies have pointed to the role of sample preparation in creating polymorphic fibrillar species. One of many potential pathways for Aß toxicity may be modulation of lipid membrane function on cellular surfaces. There are several mutations clustered around the central hydrophobic core of Aß near the a-secretase cleavage site (E22G Arctic mutation, E22K Italian mutation, D23N Iowa mutation, and A21G Flemish mutation). These point mutations are associated with hereditary diseases ranging from almost pure cerebral amyloid angiopathy (CAA) to typical Alzheimer's disease pathology with plaques and tangles. We investigated how these point mutations alter Aß aggregation in the presence of supported lipid membranes comprised of total brain lipid extract. Brain lipid extract bilayers were used as a physiologically relevant model of a neuronal cell surface. Intact lipid bilayers were exposed to predominantly monomeric preparations of Wild Type or different mutant forms of Aß, and atomic force microscopy was used to monitor aggregate formation and morphology as well as bilayer integrity over a 12 hour period. The goal of this study was to determine how point mutations in Aß, which alter peptide charge and hydrophobic character, influence interactions between Aß and the lipid surface. While fibril morphology did not appear to be significantly altered when mutants were prepped similarly and incubated under free solution conditions, aggregation in the lipid membranes resulted in a variety of polymorphic aggregates in a mutation dependent manner. The mutant peptides also had a variable ability to disrupt bilayer integrity.
Notes
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