BACE1 (beta-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes
BACE1 is a key enzyme in the generation of Abeta, the major component of senile plaques in the brains of Alzheimer's disease patients. We have generated transgenic mice expressing human BACE1 with the Cam Kinase II promoter driving neuronal-specific expression. The transgene contains the full-l...
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| Veröffentlicht in: | Molecular and cellular neuroscience 2003-11, Vol.24 (3), p.646-655 |
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| creator | Harrison, Steve M Harper, Alex J Hawkins, Julie Duddy, Graham Grau, Evelyn Pugh, Pippa L Winter, Panida H Shilliam, Claire S Hughes, Zoë A Dawson, Lee A Gonzalez, M Isabel Upton, Neil Pangalos, Menelas N Dingwall, Colin |
| description | BACE1 is a key enzyme in the generation of Abeta, the major component of senile plaques in the brains of Alzheimer's disease patients. We have generated transgenic mice expressing human BACE1 with the Cam Kinase II promoter driving neuronal-specific expression. The transgene contains the full-length coding sequence of human BACE1 preceding an internal ribosome entry site element followed by a LacZ reporter gene. These animals exhibit a bold, exploratory behavior and show elevated 5-hydroxytryptamine turnover. We have also generated a knockout mouse in which LacZ replaces the first exon of murine BACE1. Interestingly these animals show a contrasting behavior, being timid and less exploratory. Despite these clear differences both mouse lines are viable and fertile with no changes in morbidity. These results suggest an unexpected role for BACE1 in neurotransmission, perhaps through changes in amyloid precursor protein processing and Abeta levels. |
| doi_str_mv | 10.1016/s1044-7431(03)00227-6 |
| format | Article |
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We have generated transgenic mice expressing human BACE1 with the Cam Kinase II promoter driving neuronal-specific expression. The transgene contains the full-length coding sequence of human BACE1 preceding an internal ribosome entry site element followed by a LacZ reporter gene. These animals exhibit a bold, exploratory behavior and show elevated 5-hydroxytryptamine turnover. We have also generated a knockout mouse in which LacZ replaces the first exon of murine BACE1. Interestingly these animals show a contrasting behavior, being timid and less exploratory. Despite these clear differences both mouse lines are viable and fertile with no changes in morbidity. These results suggest an unexpected role for BACE1 in neurotransmission, perhaps through changes in amyloid precursor protein processing and Abeta levels.</description><identifier>ISSN: 1044-7431</identifier><identifier>DOI: 10.1016/s1044-7431(03)00227-6</identifier><identifier>PMID: 14664815</identifier><language>eng</language><publisher>United States</publisher><subject>Alzheimer Disease - enzymology ; Alzheimer Disease - genetics ; Alzheimer Disease - physiopathology ; Amyloid beta-Peptides - biosynthesis ; Amyloid Precursor Protein Secretases ; Animals ; Aspartic Acid Endopeptidases - deficiency ; Aspartic Acid Endopeptidases - genetics ; Behavior, Animal - physiology ; Brain - enzymology ; Brain - physiopathology ; Cells, Cultured ; Disease Models, Animal ; Endopeptidases ; Exploratory Behavior - physiology ; Fear - physiology ; Genes, Reporter - genetics ; Mice ; Mice, Knockout ; Mice, Transgenic ; Phenotype ; Serotonin - metabolism ; Synaptic Transmission - genetics ; Transgenes - genetics</subject><ispartof>Molecular and cellular neuroscience, 2003-11, Vol.24 (3), p.646-655</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c371t-3431b418920fb0f82a1b5c2a413dbf9365bdfecddc32802c5306094c8b89556f3</citedby><cites>FETCH-LOGICAL-c371t-3431b418920fb0f82a1b5c2a413dbf9365bdfecddc32802c5306094c8b89556f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14664815$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Harrison, Steve M</creatorcontrib><creatorcontrib>Harper, Alex J</creatorcontrib><creatorcontrib>Hawkins, Julie</creatorcontrib><creatorcontrib>Duddy, Graham</creatorcontrib><creatorcontrib>Grau, Evelyn</creatorcontrib><creatorcontrib>Pugh, Pippa L</creatorcontrib><creatorcontrib>Winter, Panida H</creatorcontrib><creatorcontrib>Shilliam, Claire S</creatorcontrib><creatorcontrib>Hughes, Zoë A</creatorcontrib><creatorcontrib>Dawson, Lee A</creatorcontrib><creatorcontrib>Gonzalez, M Isabel</creatorcontrib><creatorcontrib>Upton, Neil</creatorcontrib><creatorcontrib>Pangalos, Menelas N</creatorcontrib><creatorcontrib>Dingwall, Colin</creatorcontrib><title>BACE1 (beta-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes</title><title>Molecular and cellular neuroscience</title><addtitle>Mol Cell Neurosci</addtitle><description>BACE1 is a key enzyme in the generation of Abeta, the major component of senile plaques in the brains of Alzheimer's disease patients. We have generated transgenic mice expressing human BACE1 with the Cam Kinase II promoter driving neuronal-specific expression. The transgene contains the full-length coding sequence of human BACE1 preceding an internal ribosome entry site element followed by a LacZ reporter gene. These animals exhibit a bold, exploratory behavior and show elevated 5-hydroxytryptamine turnover. We have also generated a knockout mouse in which LacZ replaces the first exon of murine BACE1. Interestingly these animals show a contrasting behavior, being timid and less exploratory. Despite these clear differences both mouse lines are viable and fertile with no changes in morbidity. These results suggest an unexpected role for BACE1 in neurotransmission, perhaps through changes in amyloid precursor protein processing and Abeta levels.</description><subject>Alzheimer Disease - enzymology</subject><subject>Alzheimer Disease - genetics</subject><subject>Alzheimer Disease - physiopathology</subject><subject>Amyloid beta-Peptides - biosynthesis</subject><subject>Amyloid Precursor Protein Secretases</subject><subject>Animals</subject><subject>Aspartic Acid Endopeptidases - deficiency</subject><subject>Aspartic Acid Endopeptidases - genetics</subject><subject>Behavior, Animal - physiology</subject><subject>Brain - enzymology</subject><subject>Brain - physiopathology</subject><subject>Cells, Cultured</subject><subject>Disease Models, Animal</subject><subject>Endopeptidases</subject><subject>Exploratory Behavior - physiology</subject><subject>Fear - physiology</subject><subject>Genes, Reporter - genetics</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mice, Transgenic</subject><subject>Phenotype</subject><subject>Serotonin - metabolism</subject><subject>Synaptic Transmission - genetics</subject><subject>Transgenes - genetics</subject><issn>1044-7431</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUctOHDEQ9AGUJZBPAPkUsYcJ7cd4ZrjBijwkpBwgZ8v2tFnDrk1sT6T8fWZhRY6cSqqu6m5VEXLK4AsDpi4KAymbTgp2DmIJwHnXqANy9EYvyMdSHgGg5YP4QBZMKiV71h6Ren21umH03GI1TUGXZyy4pDWbWB4wBkdNHOlTTO4pTZVug8NLGkaMNfjgTA0p0uRpxCknt8Z5bjZ0xHkWannxWlybPyHlmXdrEx-wnJBDbzYFP-3xmPz6enO_-t7c_vz2Y3V12zjRsdqI-XMrWT9w8BZ8zw2zreNGMjFaPwjV2tGjG0cneA_ctQIUDNL1th_aVnlxTD6_7n3O6feEpeptKA43GxMxTUV3TM6B9N27QjZwBRyGWdi-Cl1OpWT0-jmHrcl_NQO960Lf7ULXu9A1CP3ShVaz72x_YLJbHP-79kWIf5OKh2U</recordid><startdate>200311</startdate><enddate>200311</enddate><creator>Harrison, Steve M</creator><creator>Harper, Alex J</creator><creator>Hawkins, Julie</creator><creator>Duddy, Graham</creator><creator>Grau, Evelyn</creator><creator>Pugh, Pippa L</creator><creator>Winter, Panida H</creator><creator>Shilliam, Claire S</creator><creator>Hughes, Zoë A</creator><creator>Dawson, Lee A</creator><creator>Gonzalez, M Isabel</creator><creator>Upton, Neil</creator><creator>Pangalos, Menelas N</creator><creator>Dingwall, Colin</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7X8</scope></search><sort><creationdate>200311</creationdate><title>BACE1 (beta-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes</title><author>Harrison, Steve M ; Harper, Alex J ; Hawkins, Julie ; Duddy, Graham ; Grau, Evelyn ; Pugh, Pippa L ; Winter, Panida H ; Shilliam, Claire S ; Hughes, Zoë A ; Dawson, Lee A ; Gonzalez, M Isabel ; Upton, Neil ; Pangalos, Menelas N ; Dingwall, Colin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c371t-3431b418920fb0f82a1b5c2a413dbf9365bdfecddc32802c5306094c8b89556f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Alzheimer Disease - enzymology</topic><topic>Alzheimer Disease - genetics</topic><topic>Alzheimer Disease - physiopathology</topic><topic>Amyloid beta-Peptides - biosynthesis</topic><topic>Amyloid Precursor Protein Secretases</topic><topic>Animals</topic><topic>Aspartic Acid Endopeptidases - deficiency</topic><topic>Aspartic Acid Endopeptidases - genetics</topic><topic>Behavior, Animal - physiology</topic><topic>Brain - enzymology</topic><topic>Brain - physiopathology</topic><topic>Cells, Cultured</topic><topic>Disease Models, Animal</topic><topic>Endopeptidases</topic><topic>Exploratory Behavior - physiology</topic><topic>Fear - physiology</topic><topic>Genes, Reporter - genetics</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Mice, Transgenic</topic><topic>Phenotype</topic><topic>Serotonin - metabolism</topic><topic>Synaptic Transmission - genetics</topic><topic>Transgenes - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Harrison, Steve M</creatorcontrib><creatorcontrib>Harper, Alex J</creatorcontrib><creatorcontrib>Hawkins, Julie</creatorcontrib><creatorcontrib>Duddy, Graham</creatorcontrib><creatorcontrib>Grau, Evelyn</creatorcontrib><creatorcontrib>Pugh, Pippa L</creatorcontrib><creatorcontrib>Winter, Panida H</creatorcontrib><creatorcontrib>Shilliam, Claire S</creatorcontrib><creatorcontrib>Hughes, Zoë A</creatorcontrib><creatorcontrib>Dawson, Lee A</creatorcontrib><creatorcontrib>Gonzalez, M Isabel</creatorcontrib><creatorcontrib>Upton, Neil</creatorcontrib><creatorcontrib>Pangalos, Menelas N</creatorcontrib><creatorcontrib>Dingwall, Colin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular and cellular neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Harrison, Steve M</au><au>Harper, Alex J</au><au>Hawkins, Julie</au><au>Duddy, Graham</au><au>Grau, Evelyn</au><au>Pugh, Pippa L</au><au>Winter, Panida H</au><au>Shilliam, Claire S</au><au>Hughes, Zoë A</au><au>Dawson, Lee A</au><au>Gonzalez, M Isabel</au><au>Upton, Neil</au><au>Pangalos, Menelas N</au><au>Dingwall, Colin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>BACE1 (beta-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes</atitle><jtitle>Molecular and cellular neuroscience</jtitle><addtitle>Mol Cell Neurosci</addtitle><date>2003-11</date><risdate>2003</risdate><volume>24</volume><issue>3</issue><spage>646</spage><epage>655</epage><pages>646-655</pages><issn>1044-7431</issn><abstract>BACE1 is a key enzyme in the generation of Abeta, the major component of senile plaques in the brains of Alzheimer's disease patients. We have generated transgenic mice expressing human BACE1 with the Cam Kinase II promoter driving neuronal-specific expression. The transgene contains the full-length coding sequence of human BACE1 preceding an internal ribosome entry site element followed by a LacZ reporter gene. These animals exhibit a bold, exploratory behavior and show elevated 5-hydroxytryptamine turnover. We have also generated a knockout mouse in which LacZ replaces the first exon of murine BACE1. Interestingly these animals show a contrasting behavior, being timid and less exploratory. Despite these clear differences both mouse lines are viable and fertile with no changes in morbidity. These results suggest an unexpected role for BACE1 in neurotransmission, perhaps through changes in amyloid precursor protein processing and Abeta levels.</abstract><cop>United States</cop><pmid>14664815</pmid><doi>10.1016/s1044-7431(03)00227-6</doi><tpages>10</tpages></addata></record> |
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| subjects | Alzheimer Disease - enzymology Alzheimer Disease - genetics Alzheimer Disease - physiopathology Amyloid beta-Peptides - biosynthesis Amyloid Precursor Protein Secretases Animals Aspartic Acid Endopeptidases - deficiency Aspartic Acid Endopeptidases - genetics Behavior, Animal - physiology Brain - enzymology Brain - physiopathology Cells, Cultured Disease Models, Animal Endopeptidases Exploratory Behavior - physiology Fear - physiology Genes, Reporter - genetics Mice Mice, Knockout Mice, Transgenic Phenotype Serotonin - metabolism Synaptic Transmission - genetics Transgenes - genetics |
| title | BACE1 (beta-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes |
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