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  • 1
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    Identification of a TPR-like domain in nicastrin [Biochemistry] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-05-30
    Description: The γ-secretase complex, composed of presenilin, anterior-pharynx-defective 1, nicastrin, and presenilin enhancer 2, catalyzes the intramembranous processing of a wide variety of type I membrane proteins, including amyloid precursor protein (APP) and Notch. Earlier studies have revealed that nicastrin, a type I membrane-anchored glycoprotein, plays a role in γ-secretase assembly and trafficking and has been proposed to bind substrates. To gain more insights regarding nicastrin structure and function, we generated a conformation-specific synthetic antibody and used it as a molecular probe to map functional domains within nicastrin ectodomain. The antibody bound to a conformational epitope within a nicastrin segment encompassing residues 245–630 and inhibited the processing of APP and Notch substrates in in vitro γ-secretase activity assays, suggesting that a functional domain pertinent to γ-secretase activity resides within this region. Epitope mapping and database searches revealed the presence of a structured segment, located downstream of the previously identified DAP domain (DYIGS and peptidase; residues 261–502), that is homologous to a tetratricopeptide repeat (TPR) domain commonly involved in peptide recognition. Mutagenesis analyses within the predicted TPR-like domain showed that disruption of the signature helical structure resulted in the loss of γ-secretase activity but not the assembly of the γ-secretase and that Leu571 within the TPR-like domain plays an important role in mediating substrate binding. Taken together, these studies offer provocative insights pertaining to the structural basis for nicastrin function as a “substrate receptor” within the γ-secretase complex.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 2
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    Biomedicine. A cargo receptor mystery APParently solved? (2002)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2002-02-02
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sisodia, Sangram S -- New York, N.Y. -- Science. 2002 Feb 1;295(5556):805-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Molecular Neurobiology, Chicago, IL 60637, USA. ssisodia@drugs.bsd.uchicago.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11823626" target="_blank"〉PubMed〈/a〉
    Keywords: *Adaptor Proteins, Signal Transducing ; Alzheimer Disease/etiology/metabolism ; Amyloid Precursor Protein Secretases ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/*metabolism ; Animals ; Aspartic Acid Endopeptidases/metabolism ; *Axonal Transport ; Axons/metabolism ; Brain/metabolism ; Carrier Proteins/metabolism ; Endopeptidases ; Humans ; Kinesin/chemistry/*metabolism ; Membrane Proteins/metabolism ; Mice ; Microtubule-Associated Proteins/metabolism ; Neurons/*metabolism ; Phosphorylation ; Protein Transport ; Synapses/metabolism ; Transport Vesicles/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 3
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    Neuroscience. An accomplice for gamma-secretase brought into focus (2000)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2000-10-21
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sisodia, S S -- New York, N.Y. -- Science. 2000 Sep 29;289(5488):2296-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, Pharmacology and Physiology, University of Chicago, Chicago, IL 60637, USA. ssisodia@drugs.bsd.uchicago.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11041797" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/genetics/metabolism ; Amino Acid Motifs ; Amino Acid Substitution ; Amyloid Precursor Protein Secretases ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/*metabolism ; Animals ; Aspartic Acid Endopeptidases ; Endopeptidases/genetics/*metabolism ; Endoplasmic Reticulum/metabolism ; Humans ; Membrane Proteins/chemistry/genetics/*metabolism ; Mice ; Neurons/*metabolism ; Presenilin-1 ; Presenilin-2 ; Protein Processing, Post-Translational
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
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    Genetic neurodegenerative diseases: the human illness and transgenic models (1998)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1998-11-06
    Description: Review The neurodegenerative disorders, a heterogeneous group of chronic progressive diseases, are among the most puzzling and devastating illnesses in medicine. Some of these disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis, the prion diseases, and Parkinson's disease, can occur sporadically and, in some instances, are caused by inheritance of gene mutations. Huntington's disease is acquired in an entirely genetic manner. Transgenic mice that express disease-causing genes recapitulate many features of these diseases. This review provides an overview of transgenic mouse models of familial amyotrophic lateral sclerosis, familial Alzheimer's disease, and Huntington's disease and the emerging insights relevant to the underlying molecular mechanisms of these diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Price, D L -- Sisodia, S S -- Borchelt, D R -- NS 10580/NS/NINDS NIH HHS/ -- NS 20471/NS/NINDS NIH HHS/ -- NS 37145/NS/NINDS NIH HHS/ -- etc. -- New York, N.Y. -- Science. 1998 Nov 6;282(5391):1079-83.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. dlprice@welchlink.welch.jhu.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9804539" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/genetics/metabolism/pathology ; Amino Acid Sequence ; Amyloid beta-Protein Precursor/chemistry ; Amyotrophic Lateral Sclerosis/genetics/metabolism/pathology ; Animals ; *Disease Models, Animal ; Humans ; Huntington Disease/genetics/metabolism/pathology ; Mice ; *Mice, Transgenic ; Molecular Sequence Data ; Neurodegenerative Diseases/*genetics/metabolism/pathology ; Peptides/genetics ; Trinucleotide Repeats
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 5
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    Evidence that beta-amyloid protein in Alzheimer's disease is not derived by normal processing (1990)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1990-04-27
    Description: The beta-amyloid protein (beta/A4), derived from a larger amyloid precursor protein (APP), is the principal component of senile plaques in Alzheimer's disease. APP is an integral membrane glycoprotein and is secreted as a carboxyl-terminal truncated molecule. APP cleavage, which is a membrane-associated event, occurred at a site located within the beta/A4 region. This suggests that an intact amyloidogenic beta/A4 fragment is not generated during normal APP catabolism. Therefore, an early event in amyloid formation may involve altered APP processing that results in the release and subsequent deposition of intact beta/A4.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sisodia, S S -- Koo, E H -- Beyreuther, K -- Unterbeck, A -- Price, D L -- AG 03359/AG/NIA NIH HHS/ -- AG 05146/AG/NIA NIH HHS/ -- AG 07914/AG/NIA NIH HHS/ -- etc. -- New York, N.Y. -- Science. 1990 Apr 27;248(4954):492-5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2181.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/1691865" target="_blank"〉PubMed〈/a〉
    Keywords: Aged ; Alzheimer Disease/*metabolism ; Amyloid/genetics/*metabolism ; Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Animals ; Cell Membrane ; Cells, Cultured ; Cloning, Molecular ; DNA, Recombinant ; Glycosylation ; Half-Life ; Humans ; Immunoblotting ; Molecular Weight ; Plasmids ; Protein Precursors/genetics/*metabolism ; *Protein Processing, Post-Translational ; Recombinant Fusion Proteins/metabolism ; Substance P/genetics ; Transfection
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 6
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    Comment on "ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models" (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-05-25
    Description: Cramer et al. (Reports, 23 March 2012, p. 1503; published online 9 February 2012) reported that bexarotene rapidly reduces beta-amyloid (Abeta) levels and plaque burden in two mouse models of Abeta deposition in Alzheimer's disease (AD). We now report that, although bexarotene reduces soluble Abeta40 levels in one of the mouse models, the drug has no impact on plaque burden in three strains that exhibit Abeta amyloidosis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Veeraraghavalu, Karthikeyan -- Zhang, Can -- Miller, Sean -- Hefendehl, Jasmin K -- Rajapaksha, Tharinda W -- Ulrich, Jason -- Jucker, Mathias -- Holtzman, David M -- Tanzi, Rudolph E -- Vassar, Robert -- Sisodia, Sangram S -- New York, N.Y. -- Science. 2013 May 24;340(6135):924-f. doi: 10.1126/science.1235505.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, University of Chicago, Chicago, IL 60637, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23704555" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/*drug therapy/*metabolism ; Amyloid beta-Peptides/*metabolism ; Animals ; Apolipoproteins E/*metabolism ; Brain/*metabolism ; Male ; Tetrahydronaphthalenes/*pharmacology/*therapeutic use
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 7
    Electronic Resource
    Electronic Resource
    Studies on the Metabolism and Biological Function of APLP2 (1996)
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 777 (1996), S. 0 
    Details
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Notes: Amyloid precursor proteins (APP) are a member of a larger family of proteins that include the amyloid precursor-like proteins (APLP) APLP1 and APLP2. We have examined the expression and metabolism of APLP2 and document that APLP2 is expressed at high levels in the nervous system and in peripheral tissues. Furthermore, several APLP2 isoforms encoded by alternatively spliced transcripts are posttranslationally modified by a chondroitin sulfate glycosaminoglycan (CSGAG) chain. Furthermore, CSGAG modification is regulated by the insertion of sequences encoded by an alternatively spliced exon. Notably, expression of the CSGAG form of APLP2 appears restricted to embryonic neurons and mature neuronal populations that undergo regeneration, such as olfactory sensory neurons. Thus, differences in posttranslational modifications between the APLP2 isoforms and APP are likely to underlie differences in the regulation and function of these homologues. Our present efforts are directed towards using gene targeting strategies to disrupt the expression of the mouse APP/APLP2 genes to define the normative roles of the encoded molecules in development, plasticity, regeneration, and repair.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1749-6632.1996.tb34404.x
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  • 8
    Electronic Resource
    Electronic Resource
    Mice Deficient for the Amyloid Precursor Protein Gene (1996)
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 777 (1996), S. 0 
    Details
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Notes: To understand the in vivo function of the amyloid precursor protein (APP) we generated an APP null mutation in mice by homologous recombination in embryonic stem (ES) cells. We show here that homozygous APP deficient mice were produced at expected frequencies. Neither APP mRNA nor protein could be detected in these animals. Yet the homozygous APP mutant mice are fertile and do not show overt abnormalities at up to 12 weeks of age. Neuroanatomical studies of the brain did not reveal significant differences in the knockout mice as compared to the wild-type controls. These results argue against an essential function of APP in mouse embryonic and early neuronal development.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1749-6632.1996.tb34456.x
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  • 9
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    Activation and intrinsic  -secretase activity of presenilin 1 (2010)
    National Academy of Sciences
    Details
    Publication Date: 2010-11-29
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 10
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    Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. (1990)
    National Academy of Sciences
    Details
    Publication Date: 1990-02-01
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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