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
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/22687
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/22687
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling 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 Técnicas2025-10-22T11:10:13Zoai: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:34982025-10-22 11:10:13.468CONICET 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
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1846781461428961280
score 12.982451

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