Presenilin-1 280Glu-->Ala mutation alters C-terminal APP processing yielding longer abeta peptides: implications for Alzheimer's disease
- Autores
- Van Vickle, Gregory D.; Esh, Chera L.; Kokjohn, Tyler A.; Patton, R. Lyle; Kalback, Walter M.; Luehrs, Dean C.; Beach, Thomas G.; Newel, Amanda J.; Lopera, Francisco; Ghetti, Bernardino; Vidal, Rubén Alejandro; Castaño, Eduardo Miguel; Roher, Alex E.
- Año de publicación
- 2008
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Presenilin (PS) mutations enhance the production of the Abeta42 peptide that is derived from the amyloid precursor protein (APP). The pathway(s) by which the Abeta42 species is preferentially produced has not been elucidated, nor is the mechanism by which PS mutations produce early-onset dementia established. Using a combination of histological, immunohistochemical, biochemical, and mass spectrometric methods, we examined the structural and morphological nature of the amyloid species produced in a patient expressing the PS1 280Glu-->Ala familial Alzheimer's disease mutation. Abundant diffuse plaques were observed that exhibited a staining pattern and morphology distinct from previously described PS cases, as well as discreet amyloid plaques within the white matter. In addition to finding increased amounts of CT99 and Abeta42 peptides, our investigation revealed the presence of a complex array of Abeta peptides substantially longer than 42/43 amino acid residue species. The increased hydrophobic nature of longer Abeta species retained within the membrane walls could impact the structure and function of plasma membrane and organelles. These C-terminally longer peptides may, through steric effects, dampen the rate of turnover by critical amyloid degrading enzymes such as neprilysin and insulin degrading enzyme. A complete understanding of the deleterious side effects of membrane bound Abeta as a consequence of gamma-secretase alterations is needed to understand Alzheimer's disease pathophysiology and will aid in the design of therapeutic interventions.
Fil: Van Vickle, Gregory D.. Sun Health Research Institute; Estados Unidos
Fil: Esh, Chera L.. Sun Health Research Institute; Estados Unidos
Fil: Kokjohn, Tyler A.. Sun Health Research Institute; Estados Unidos
Fil: Patton, R. Lyle. Sun Health Research Institute; Estados Unidos
Fil: Kalback, Walter M.. Sun Health Research Institute; Estados Unidos
Fil: Luehrs, Dean C.. Sun Health Research Institute; Estados Unidos
Fil: Beach, Thomas G.. Sun Health Research Institute; Estados Unidos
Fil: Newel, Amanda J.. Sun Health Research Institute; Estados Unidos
Fil: Lopera, Francisco. Universidad de Antioquía; Colombia
Fil: Ghetti, Bernardino. Indiana University; Estados Unidos
Fil: Vidal, Rubén Alejandro. Indiana University; Estados Unidos
Fil: Castaño, Eduardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Roher, Alex E.. Sun Health Research Institute; Estados Unidos - Materia
-
presenilin
mutations
transgenic mice - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/22687
Ver los metadatos del registro completo
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Presenilin-1 280Glu-->Ala mutation alters C-terminal APP processing yielding longer abeta peptides: implications for Alzheimer's diseaseVan Vickle, Gregory D.Esh, Chera L.Kokjohn, Tyler A.Patton, R. LyleKalback, Walter M.Luehrs, Dean C.Beach, Thomas G.Newel, Amanda J.Lopera, FranciscoGhetti, BernardinoVidal, Rubén AlejandroCastaño, Eduardo MiguelRoher, Alex E.presenilinmutationstransgenic micehttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Presenilin (PS) mutations enhance the production of the Abeta42 peptide that is derived from the amyloid precursor protein (APP). The pathway(s) by which the Abeta42 species is preferentially produced has not been elucidated, nor is the mechanism by which PS mutations produce early-onset dementia established. Using a combination of histological, immunohistochemical, biochemical, and mass spectrometric methods, we examined the structural and morphological nature of the amyloid species produced in a patient expressing the PS1 280Glu-->Ala familial Alzheimer's disease mutation. Abundant diffuse plaques were observed that exhibited a staining pattern and morphology distinct from previously described PS cases, as well as discreet amyloid plaques within the white matter. In addition to finding increased amounts of CT99 and Abeta42 peptides, our investigation revealed the presence of a complex array of Abeta peptides substantially longer than 42/43 amino acid residue species. The increased hydrophobic nature of longer Abeta species retained within the membrane walls could impact the structure and function of plasma membrane and organelles. These C-terminally longer peptides may, through steric effects, dampen the rate of turnover by critical amyloid degrading enzymes such as neprilysin and insulin degrading enzyme. A complete understanding of the deleterious side effects of membrane bound Abeta as a consequence of gamma-secretase alterations is needed to understand Alzheimer's disease pathophysiology and will aid in the design of therapeutic interventions.Fil: Van Vickle, Gregory D.. Sun Health Research Institute; Estados UnidosFil: Esh, Chera L.. Sun Health Research Institute; Estados UnidosFil: Kokjohn, Tyler A.. Sun Health Research Institute; Estados UnidosFil: Patton, R. Lyle. Sun Health Research Institute; Estados UnidosFil: Kalback, Walter M.. Sun Health Research Institute; Estados UnidosFil: Luehrs, Dean C.. Sun Health Research Institute; Estados UnidosFil: Beach, Thomas G.. Sun Health Research Institute; Estados UnidosFil: Newel, Amanda J.. Sun Health Research Institute; Estados UnidosFil: Lopera, Francisco. Universidad de Antioquía; ColombiaFil: Ghetti, Bernardino. Indiana University; Estados UnidosFil: Vidal, Rubén Alejandro. Indiana University; Estados UnidosFil: Castaño, Eduardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Roher, Alex E.. Sun Health Research Institute; Estados UnidosFeinstein Institute for Medical Research2008-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/22687Van Vickle, Gregory D.; Esh, Chera L.; Kokjohn, Tyler A.; Patton, R. Lyle; Kalback, Walter M.; et al.; Presenilin-1 280Glu-->Ala mutation alters C-terminal APP processing yielding longer abeta peptides: implications for Alzheimer's disease; Feinstein Institute for Medical Research; Molecular Medicine; 14; 3-4; 3-2008; 184-1941076-15511528-3658CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2258166/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:41:40Zoai:ri.conicet.gov.ar:11336/22687instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:41:40.822CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Presenilin-1 280Glu-->Ala mutation alters C-terminal APP processing yielding longer abeta peptides: implications for Alzheimer's disease |
title |
Presenilin-1 280Glu-->Ala mutation alters C-terminal APP processing yielding longer abeta peptides: implications for Alzheimer's disease |
spellingShingle |
Presenilin-1 280Glu-->Ala mutation alters C-terminal APP processing yielding longer abeta peptides: implications for Alzheimer's disease Van Vickle, Gregory D. presenilin mutations transgenic mice |
title_short |
Presenilin-1 280Glu-->Ala mutation alters C-terminal APP processing yielding longer abeta peptides: implications for Alzheimer's disease |
title_full |
Presenilin-1 280Glu-->Ala mutation alters C-terminal APP processing yielding longer abeta peptides: implications for Alzheimer's disease |
title_fullStr |
Presenilin-1 280Glu-->Ala mutation alters C-terminal APP processing yielding longer abeta peptides: implications for Alzheimer's disease |
title_full_unstemmed |
Presenilin-1 280Glu-->Ala mutation alters C-terminal APP processing yielding longer abeta peptides: implications for Alzheimer's disease |
title_sort |
Presenilin-1 280Glu-->Ala mutation alters C-terminal APP processing yielding longer abeta peptides: implications for Alzheimer's disease |
dc.creator.none.fl_str_mv |
Van Vickle, Gregory D. Esh, Chera L. Kokjohn, Tyler A. Patton, R. Lyle Kalback, Walter M. Luehrs, Dean C. Beach, Thomas G. Newel, Amanda J. Lopera, Francisco Ghetti, Bernardino Vidal, Rubén Alejandro Castaño, Eduardo Miguel Roher, Alex E. |
author |
Van Vickle, Gregory D. |
author_facet |
Van Vickle, Gregory D. Esh, Chera L. Kokjohn, Tyler A. Patton, R. Lyle Kalback, Walter M. Luehrs, Dean C. Beach, Thomas G. Newel, Amanda J. Lopera, Francisco Ghetti, Bernardino Vidal, Rubén Alejandro Castaño, Eduardo Miguel Roher, Alex E. |
author_role |
author |
author2 |
Esh, Chera L. Kokjohn, Tyler A. Patton, R. Lyle Kalback, Walter M. Luehrs, Dean C. Beach, Thomas G. Newel, Amanda J. Lopera, Francisco Ghetti, Bernardino Vidal, Rubén Alejandro Castaño, Eduardo Miguel Roher, Alex E. |
author2_role |
author author author author author author author author author author author author |
dc.subject.none.fl_str_mv |
presenilin mutations transgenic mice |
topic |
presenilin mutations transgenic mice |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
dc.description.none.fl_txt_mv |
Presenilin (PS) mutations enhance the production of the Abeta42 peptide that is derived from the amyloid precursor protein (APP). The pathway(s) by which the Abeta42 species is preferentially produced has not been elucidated, nor is the mechanism by which PS mutations produce early-onset dementia established. Using a combination of histological, immunohistochemical, biochemical, and mass spectrometric methods, we examined the structural and morphological nature of the amyloid species produced in a patient expressing the PS1 280Glu-->Ala familial Alzheimer's disease mutation. Abundant diffuse plaques were observed that exhibited a staining pattern and morphology distinct from previously described PS cases, as well as discreet amyloid plaques within the white matter. In addition to finding increased amounts of CT99 and Abeta42 peptides, our investigation revealed the presence of a complex array of Abeta peptides substantially longer than 42/43 amino acid residue species. The increased hydrophobic nature of longer Abeta species retained within the membrane walls could impact the structure and function of plasma membrane and organelles. These C-terminally longer peptides may, through steric effects, dampen the rate of turnover by critical amyloid degrading enzymes such as neprilysin and insulin degrading enzyme. A complete understanding of the deleterious side effects of membrane bound Abeta as a consequence of gamma-secretase alterations is needed to understand Alzheimer's disease pathophysiology and will aid in the design of therapeutic interventions. Fil: Van Vickle, Gregory D.. Sun Health Research Institute; Estados Unidos Fil: Esh, Chera L.. Sun Health Research Institute; Estados Unidos Fil: Kokjohn, Tyler A.. Sun Health Research Institute; Estados Unidos Fil: Patton, R. Lyle. Sun Health Research Institute; Estados Unidos Fil: Kalback, Walter M.. Sun Health Research Institute; Estados Unidos Fil: Luehrs, Dean C.. Sun Health Research Institute; Estados Unidos Fil: Beach, Thomas G.. Sun Health Research Institute; Estados Unidos Fil: Newel, Amanda J.. Sun Health Research Institute; Estados Unidos Fil: Lopera, Francisco. Universidad de Antioquía; Colombia Fil: Ghetti, Bernardino. Indiana University; Estados Unidos Fil: Vidal, Rubén Alejandro. Indiana University; Estados Unidos Fil: Castaño, Eduardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Roher, Alex E.. Sun Health Research Institute; Estados Unidos |
description |
Presenilin (PS) mutations enhance the production of the Abeta42 peptide that is derived from the amyloid precursor protein (APP). The pathway(s) by which the Abeta42 species is preferentially produced has not been elucidated, nor is the mechanism by which PS mutations produce early-onset dementia established. Using a combination of histological, immunohistochemical, biochemical, and mass spectrometric methods, we examined the structural and morphological nature of the amyloid species produced in a patient expressing the PS1 280Glu-->Ala familial Alzheimer's disease mutation. Abundant diffuse plaques were observed that exhibited a staining pattern and morphology distinct from previously described PS cases, as well as discreet amyloid plaques within the white matter. In addition to finding increased amounts of CT99 and Abeta42 peptides, our investigation revealed the presence of a complex array of Abeta peptides substantially longer than 42/43 amino acid residue species. The increased hydrophobic nature of longer Abeta species retained within the membrane walls could impact the structure and function of plasma membrane and organelles. These C-terminally longer peptides may, through steric effects, dampen the rate of turnover by critical amyloid degrading enzymes such as neprilysin and insulin degrading enzyme. A complete understanding of the deleterious side effects of membrane bound Abeta as a consequence of gamma-secretase alterations is needed to understand Alzheimer's disease pathophysiology and will aid in the design of therapeutic interventions. |
publishDate |
2008 |
dc.date.none.fl_str_mv |
2008-03 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/22687 Van Vickle, Gregory D.; Esh, Chera L.; Kokjohn, Tyler A.; Patton, R. Lyle; Kalback, Walter M.; et al.; Presenilin-1 280Glu-->Ala mutation alters C-terminal APP processing yielding longer abeta peptides: implications for Alzheimer's disease; Feinstein Institute for Medical Research; Molecular Medicine; 14; 3-4; 3-2008; 184-194 1076-1551 1528-3658 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/22687 |
identifier_str_mv |
Van Vickle, Gregory D.; Esh, Chera L.; Kokjohn, Tyler A.; Patton, R. Lyle; Kalback, Walter M.; et al.; Presenilin-1 280Glu-->Ala mutation alters C-terminal APP processing yielding longer abeta peptides: implications for Alzheimer's disease; Feinstein Institute for Medical Research; Molecular Medicine; 14; 3-4; 3-2008; 184-194 1076-1551 1528-3658 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2258166/ |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
Feinstein Institute for Medical Research |
publisher.none.fl_str_mv |
Feinstein Institute for Medical Research |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) |
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CONICET Digital (CONICET) |
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Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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1844613314815983616 |
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13.070432 |