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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

Does ß-APP staining of the brain in infant bed-sharing deaths differentiate these cases from sudden infant death syndrome?

https://arctichealth.org/en/permalink/ahliterature263798
Source
J Forensic Leg Med. 2014 Oct;27:46-9
Publication Type
Article
Date
Oct-2014
Author
Lisbeth Lund Jensen
Jytte Banner
Roger W Byard
Source
J Forensic Leg Med. 2014 Oct;27:46-9
Date
Oct-2014
Language
English
Publication Type
Article
Keywords
Amyloid beta-Protein Precursor - metabolism
Australia
Beds
Brain - metabolism
Denmark
Female
Forensic Pathology
Humans
Infant
Male
Sex Distribution
Sleep
Staining and Labeling
Sudden Infant Death
Abstract
Archival cerebral tissue from infants whose deaths were attributed to sudden infant death syndrome (SIDS) from South Australia and Western Denmark were stained for ß-amyloid precursor protein (ß-APP) and graded according to a simple scoring chart. The resulting APP scores were correlated with sleeping situation (shared vs. alone) showing a significantly higher amount of ß-APP staining in the non-bed-sharing, than in the bed-sharing infants (Mann-Whitney, Australia: p = 0.0128, Denmark: p = 0.0014, Combined: p = 0.0031). There was also a marked but non-significant difference in sex distribution between bed-sharers and non-bed-sharers with a male to female ratio of 1:1 in the first group and 2:1 in the latter. Of 48 Australian and 76 Danish SIDS infants, ß-APP staining was present in 116 (94%) cases. The eight negative cases were all from the Danish cohort. This study has shown that the amount of ß-APP staining was significantly higher in infants who were sleeping alone compared to those who were bed-sharing with one or more adults, in both an Australian and Danish cohort of SIDS infants. Whether this results from differences in the speed with which these infants die, differences in lethal mechanisms involving possible accidental asphyxiation in shared sleepers, or differences in the number of previous hypoxic-ischemic events, remains to be clarified.
PubMed ID
25287799 View in PubMed
Less detail

Inhibition of GSK-3 ameliorates Abeta pathology in an adult-onset Drosophila model of Alzheimer's disease.

https://arctichealth.org/en/permalink/ahliterature100428
Source
PLoS Genet. 2010;6(9)
Publication Type
Article
Date
2010
Author
Oyinkan Sofola
Fiona Kerr
Iain Rogers
Richard Killick
Hrvoje Augustin
Carina Gandy
Marcus J Allen
John Hardy
Simon Lovestone
Linda Partridge
Author Affiliation
Department of Genetics, Evolution, and Environment, Institute of Healthy Ageing and Research, University College London, London, United Kingdom.
Source
PLoS Genet. 2010;6(9)
Date
2010
Language
English
Publication Type
Article
Keywords
Aging - drug effects - pathology
Alzheimer Disease - enzymology - mortality - pathology - physiopathology
Amyloid beta-Protein Precursor - metabolism - toxicity
Animals
Disease Models, Animal
Drosophila Proteins - antagonists & inhibitors - metabolism
Drosophila melanogaster - drug effects - enzymology
Genes, Dominant - genetics
Glycogen Synthase Kinase 3 - antagonists & inhibitors - metabolism
Humans
Lithium - pharmacology
Mutant Proteins - toxicity
Nervous System - drug effects - metabolism - pathology
Neurons - drug effects - enzymology - pathology
Peptides - toxicity
Phosphorylation - drug effects
Phosphoserine - metabolism
tau Proteins - metabolism
Abstract
Abeta peptide accumulation is thought to be the primary event in the pathogenesis of Alzheimer's disease (AD), with downstream neurotoxic effects including the hyperphosphorylation of tau protein. Glycogen synthase kinase-3 (GSK-3) is increasingly implicated as playing a pivotal role in this amyloid cascade. We have developed an adult-onset Drosophila model of AD, using an inducible gene expression system to express Arctic mutant Abeta42 specifically in adult neurons, to avoid developmental effects. Abeta42 accumulated with age in these flies and they displayed increased mortality together with progressive neuronal dysfunction, but in the apparent absence of neuronal loss. This fly model can thus be used to examine the role of events during adulthood and early AD aetiology. Expression of Abeta42 in adult neurons increased GSK-3 activity, and inhibition of GSK-3 (either genetically or pharmacologically by lithium treatment) rescued Abeta42 toxicity. Abeta42 pathogenesis was also reduced by removal of endogenous fly tau; but, within the limits of detection of available methods, tau phosphorylation did not appear to be altered in flies expressing Abeta42. The GSK-3-mediated effects on Abeta42 toxicity appear to be at least in part mediated by tau-independent mechanisms, because the protective effect of lithium alone was greater than that of the removal of tau alone. Finally, Abeta42 levels were reduced upon GSK-3 inhibition, pointing to a direct role of GSK-3 in the regulation of Abeta42 peptide level, in the absence of APP processing. Our study points to the need both to identify the mechanisms by which GSK-3 modulates Abeta42 levels in the fly and to determine if similar mechanisms are present in mammals, and it supports the potential therapeutic use of GSK-3 inhibitors in AD.
PubMed ID
20824130 View in PubMed
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Melatonin receptor type 1A gene linked to Alzheimer's disease in old age.

https://arctichealth.org/en/permalink/ahliterature299161
Source
Sleep. 2018 07 01; 41(7):
Publication Type
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Date
07-01-2018
Author
Sonja Sulkava
Pranuthi Muggalla
Raimo Sulkava
Hanna M Ollila
Terhi Peuralinna
Liisa Myllykangas
Karri Kaivola
David J Stone
Bryan J Traynor
Alan E Renton
Alberto M Rivera
Seppo Helisalmi
Hilkka Soininen
Tuomo Polvikoski
Mikko Hiltunen
Pentti J Tienari
Henri J Huttunen
Tiina Paunio
Author Affiliation
Department of Health, Genomics and Biomarkers Unit, National Institute for Health and Welfare, Helsinki, Finland.
Source
Sleep. 2018 07 01; 41(7):
Date
07-01-2018
Language
English
Publication Type
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Keywords
Aged, 80 and over
Alzheimer Disease - genetics - pathology
Amyloid beta-Peptides - metabolism
Amyloid beta-Protein Precursor - metabolism
Brain - metabolism - pathology
Case-Control Studies
Circadian Rhythm
Cohort Studies
Female
Finland
Genetic Predisposition to Disease
Humans
In Vitro Techniques
Male
Melatonin - metabolism
Neurofibrillary Tangles - genetics - pathology
Neurons - metabolism
Plaque, Amyloid - genetics - pathology
Receptor, Melatonin, MT1 - genetics - metabolism
Receptors, Melatonin
Abstract
Disruption of the circadian rhythms is a frequent preclinical and clinical manifestation of Alzheimer's disease. Furthermore, it has been suggested that shift work is a risk factor for Alzheimer's disease. Previously, we have reported association of intolerance to shift work (job-related exhaustion in shift workers) with a variant rs12506228A, which is situated close to melatonin receptor type 1A gene (MTNR1A) and linked to MTNR1A brain expression levels. Here, we studied association of that variant with clinical and neuropathological Alzheimer's disease in a Finnish whole-population cohort Vantaa 85+ (n = 512, participants over 85 years) and two follow-up cohorts. Rs12506228A was associated with clinical Alzheimer's disease (p = 0.000073). Analysis of post-mortem brain tissues showed association with higher amount of neurofibrillary tangles (p = 0.0039) and amyloid beta plaques (p = 0.0041). We then followed up the associations in two independent replication samples. Replication for the association with clinical Alzheimer's disease was detected in Kuopio 75+ (p = 0.012, n = 574), but not in the younger case-control sample (n = 651 + 669). While melatonin has been established in regulation of circadian rhythms, an independent role has been also shown for neuroprotection and specifically for anti-amyloidogenic effects. Indeed, in vitro, RNAi mediated silencing of MTNR1A increased the amyloidogenic processing of amyloid precursor protein (APP) in neurons, whereas overexpression decreased it. Our findings suggest variation close to MTNR1A as a shared genetic risk factor for intolerance to shift work and Alzheimer's disease in old age. The genetic associations are likely to be mediated by differences in MTNR1A expression, which, in turn, modulate APP metabolism.
PubMed ID
29982836 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

Screening for amyloid beta precursor protein codon 665, 670/671 and 717 mutations in Finnish patients with Alzheimer's disease.

https://arctichealth.org/en/permalink/ahliterature212639
Source
Neurosci Lett. 1996 Feb 16;205(1):68-70
Publication Type
Article
Date
Feb-16-1996
Author
S. Helisalmi
A. Mannermaa
M. Lehtovirta
M. Ryynänen
P. Riekkinen
H. Soininen
Author Affiliation
Department of Neurology, University of Kuopio, Finland. helisalm@uku.fi
Source
Neurosci Lett. 1996 Feb 16;205(1):68-70
Date
Feb-16-1996
Language
English
Publication Type
Article
Keywords
Age of Onset
Aged
Alzheimer Disease - genetics - metabolism
Amyloid beta-Protein Precursor - metabolism
Diagnosis, Differential
Finland
Humans
Middle Aged
Mutation
Abstract
In this study, we screened for the amyloid beta precursor protein (APP) 665 (glutamic acid to aspartic acid), 670/671 (lysine to asparagine and methionine to leucine) and 717 (valine to isoleucine) mutations in 34 persons affected with familial Alzheimer's disease (AD) and 139 with sporadic AD, originating from eastern Finland, using polymerase chain reaction amplification and restriction enzyme digestion. We did not find any of these mutations in the APP gene in our study. We conclude that these mutations in the APP gene may be a very rare cause of AD in Eastern Finland and thus most Finnish familial AD will likely be due to other gene defects.
PubMed ID
8867023 View in PubMed
Less detail

Vascular ß-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAß mice.

https://arctichealth.org/en/permalink/ahliterature133606
Source
Acta Neuropathol. 2011 Sep;122(3):293-311
Publication Type
Article
Date
Sep-2011
Author
Mario Merlini
Eric P Meyer
Alexandra Ulmann-Schuler
Roger M Nitsch
Author Affiliation
Division of Psychiatry Research, University of Zürich, August Forel-Strasse 1, 8008, Zurich, Switzerland. mario.merlini@gladstone.ucsf.edu
Source
Acta Neuropathol. 2011 Sep;122(3):293-311
Date
Sep-2011
Language
English
Publication Type
Article
Keywords
Amyloid beta-Peptides - genetics - metabolism
Amyloid beta-Protein Precursor - metabolism
Animals
Antigens, CD31 - metabolism
Astrocytes - drug effects - metabolism - pathology - ultrastructure
Basement Membrane - metabolism - pathology
Blood-Brain Barrier - pathology - physiopathology
Brain - pathology
Cell Culture Techniques
Cerebral Amyloid Angiopathy - complications - genetics - pathology
Cerebral Arteries - metabolism - pathology - ultrastructure
Cerebrovascular Disorders - etiology - pathology
Disease Models, Animal
Disease Progression
Dystroglycans - metabolism
Endothelium - metabolism - pathology
Gene Expression Regulation - genetics
Glial Fibrillary Acidic Protein - metabolism
Glucose - metabolism
Glucose Transporter Type 1 - genetics - metabolism
Hemorrhage - etiology - metabolism - pathology
Humans
Lactase - metabolism
Laminin - metabolism
Mice
Mice, Transgenic
Microdialysis - methods
Microscopy, Electron, Scanning - methods
Monocarboxylic Acid Transporters - genetics - metabolism
Muscle, Smooth - metabolism - pathology - ultrastructure
Plaque, Amyloid - metabolism - pathology
Symporters - genetics - metabolism
Abstract
Cerebrovascular lesions related to congophilic amyloid angiopathy (CAA) often accompany deposition of ?-amyloid (A?) in Alzheimer's disease (AD), leading to disturbed cerebral blood flow and cognitive dysfunction, posing the question how cerebrovascular pathology contributes to the pathology of AD. To address this question, we characterised the morphology, biochemistry and functionality of brain blood vessels in transgenic arctic ?-amyloid (arcA?) mice expressing human amyloid precursor protein (APP) with both the familial AD-causing Swedish and Arctic mutations; these mice are characterised by strong CAA pathology. Mice were analysed at early, mid and late-stage pathology. Expression of the glucose transporter GLUT1 at the blood-brain barrier (BBB) was significantly decreased and paralleled by impaired in vivo blood-to-brain glucose transport and reduced cerebral lactate release during neuronal activation from mid-stage pathology onwards. Reductions in astrocytic GLUT1 and lactate transporters, as well as retraction of astrocyte endfeet and swelling consistent with neurovascular uncoupling, preceded wide-spread ?-amyloid plaque pathology. We show that CAA at later disease stages is accompanied by severe morphological alterations of brain blood vessels including stenoses, BBB leakages and the loss of vascular smooth muscle cells (SMCs). Together, our data establish that cerebrovascular and astrocytic pathology are paralleled by impaired cerebral metabolism in arcA? mice, and that astrocyte alterations occur already at premature stages of pathology, suggesting that astrocyte dysfunction can contribute to early behavioural and cognitive impairments seen in these mice.
Notes
Cites: FASEB J. 2010 Jan;24(1):229-4119770225
Cites: J Neurochem. 2008 Nov;107(3):789-9818761711
Cites: Neurodegener Dis. 2010;7(1-3):116-2120173340
Cites: Neurobiol Aging. 2011 Feb;32(2):280-9219329229
Cites: Trends Neurosci. 2011 Feb;34(2):76-8721236501
Cites: Neurobiol Aging. 2012 Feb;33(2):423.e1-1321051108
Cites: Am J Pathol. 2000 Oct;157(4):1283-9811021833
Cites: Neuroscience. 2000;100(3):617-2711098125
Cites: J Neurosci. 2001 Mar 1;21(5):1619-2711222652
Cites: Prog Neurobiol. 2001 Aug;64(6):575-61111311463
Cites: Nat Neurosci. 2001 Sep;4(9):887-9311528419
Cites: J Neurosci Res. 2001 Dec 1;66(5):824-3811746408
Cites: J Neurosci Res. 2002 Jul 15;69(2):243-5612111806
Cites: Lancet. 2003 Feb 15;361(9357):605-812598159
Cites: Neurobiol Aging. 2003 May-Jun;24(3):437-5112600720
Cites: Neurosci Lett. 2004 Jan 23;355(1-2):105-814729246
Cites: Neurobiol Aging. 2004 May-Jun;25(5):599-602; discussion 603-415172735
Cites: Acta Neuropathol. 1976 Mar 15;34(2):125-361258608
Cites: J Cell Physiol. 1981 May;107(2):171-837251679
Cites: J Cereb Blood Flow Metab. 1988 Feb;8(1):130-73339103
Cites: J Neurochem. 1989 Oct;53(4):1083-82769254
Cites: Glia. 1991;4(1):11-241828781
Cites: Prog Neurobiol. 2008 Dec 11;86(4):342-6718948166
Cites: J Neurosci Res. 1994 Feb 1;37(2):197-2078151728
Cites: Ann Neurol. 1994 May;35(5):546-518179300
Cites: Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10625-97938003
Cites: J Neuropathol Exp Neurol. 1994 Nov;53(6):637-457964904
Cites: Eur J Neurosci. 1996 Dec;8(12):2739-478996823
Cites: Brain. 1998 Apr;121 ( Pt 4):611-319577389
Cites: Am J Pathol. 1998 Sep;153(3):725-339736023
Cites: FEBS J. 2009 Feb;276(4):995-100619215301
Cites: Radiology. 2009 Mar;250(3):856-6619164119
Cites: Acta Neuropathol. 2009 May;117(5):557-6719221770
Cites: Neuroscience. 2009 Mar 31;159(3):1055-6919356689
Cites: Acta Neuropathol. 2009 Jul;118(1):87-10219234858
Cites: Acta Neuropathol. 2009 Jul;118(1):103-1319319544
Cites: Int J Mol Sci. 2009 Apr;10(4):1872-9519468344
Cites: Nat Rev Neurol. 2009 Jun;5(6):305-619498432
Cites: Stroke. 2009 Jul;40(7):2601-619443808
Cites: Acta Neuropathol. 2009 Aug;118(2):219-3319533155
Cites: Curr Med Chem. 2009;16(20):2498-51319601795
Cites: Neurobiol Aging. 2009 Sep;30(9):1512-418187235
Cites: Neuropharmacology. 2009 Mar;56(4):808-1319705573
Cites: Nat Rev Immunol. 2009 Jun;9(6):449-5619424277
Cites: FEBS Lett. 1998 Oct 9;436(3):445-89801166
Cites: J Neurosci. 1999 Jan 1;19(1):34-99870935
Cites: Dement Geriatr Cogn Disord. 2005;19(1):1-1015383738
Cites: Neurobiol Dis. 2005 Apr;18(3):459-6515755672
Cites: Trends Neurosci. 2005 Apr;28(4):202-815808355
Cites: Cardiovasc Diabetol. 2005;4(1):915985157
Cites: Mol Neurobiol. 2005 Aug;32(1):59-7216077184
Cites: J Cereb Blood Flow Metab. 2006 Jan;26(1):142-5215973352
Cites: Nat Rev Neurosci. 2006 Jan;7(1):41-5316371949
Cites: J Exp Med. 2006 Apr 17;203(4):1007-1916585265
Cites: Mol Ther. 2006 Jul;14(1):69-7816650807
Cites: Biochemistry. 2007 Apr 3;46(13):3966-7417348688
Cites: Neurobiol Aging. 2007 Sep;28(9):1297-30616876915
Cites: J Cereb Blood Flow Metab. 2007 Nov;27(11):1766-9117579656
Cites: Nat Neurosci. 2007 Nov;10(11):1369-7617965657
Cites: Brain Res. 2007 Nov 21;1181:93-10317916337
Cites: Neuron. 2008 Jan 24;57(2):178-20118215617
Cites: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3587-9218305170
Cites: Acta Neuropathol. 2008 Jun;115(6):599-60918369648
Cites: Neurobiol Aging. 2010 Apr;31(4):578-9018586353
PubMed ID
21688176 View in PubMed
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7 records – page 1 of 1.