Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations

Autores
Maarouf, Chera L.; Daugs, Ian D.; Spina, Salvatore; Vidal, Ruben; Kokjohn, Tyler A.; Patton, R. Lyle; Kalback, Walter M.; Luehrs, Dean C.; Walker, Douglas G.; Castaño, Eduardo Miguel; Beach, Thomas G.; Ghetti, Bernardino; Roher, Alex E.
Año de publicación
2008
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
BACKGROUND: Mutations in the presenilin (PSEN) genes are associated with early-onset familial Alzheimer's disease (FAD). Biochemical characterizations and comparisons have revealed that many PSEN mutations alter gamma-secretase activity to promote accumulation of toxic Abeta42 peptides. In this study, we compared the histopathologic and biochemical profiles of ten FAD cases expressing independent PSEN mutations and determined the degradation patterns of amyloid-beta precursor protein (AbetaPP), Notch, N-cadherin and Erb-B4 by gamma-secretase. In addition, the levels of Abeta40/42 peptides were quantified by ELISA. RESULTS: We observed a wide variation in type, number and distribution of amyloid deposits and neurofibrillary tangles. Four of the ten cases examined exhibited a substantial enrichment in the relative proportions of Abeta40 over Abeta42. The AbetaPP N-terminal and C-terminal fragments and Tau species, assessed by Western blots and scanning densitometry, also demonstrated a wide variation. The Notch-1 intracellular domain was negligible by Western blotting in seven PSEN cases. There was significant N-cadherin and Erb-B4 peptide heterogeneity among the different PSEN mutations. CONCLUSION: These observations imply that missense mutations in PSEN genes can alter a range of key gamma-secretase activities to produce an array of subtly different biochemical, neuropathological and clinical manifestations. Beyond the broad common features of dementia, plaques and tangles, the various PSEN mutations resulted in a wide heterogeneity and complexity and differed from sporadic AD.
Fil: Maarouf, Chera L.. Sun Health Research Institute; Estados Unidos
Fil: Daugs, Ian D.. Sun Health Research Institute; Estados Unidos
Fil: Spina, Salvatore. Universita Degli Studi Di Siena; Italia. Indiana University; Estados Unidos
Fil: Vidal, Ruben. Indiana University; Estados Unidos
Fil: Kokjohn, Tyler A.. Sun Health Research Institute; Estados Unidos. Midwestern University; 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: Walker, Douglas G.. Sun Health Research Institute; 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: Beach, Thomas G.. Sun Health Research Institute; Estados Unidos
Fil: Ghetti, Bernardino. Indiana University; Estados Unidos
Fil: Roher, Alex E.. Sun Health Research Institute; Estados Unidos
Materia
presenilin
FAD
mutations
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:11336/21115
Acceder
id CONICETDig_f04833fe7816b31aaa83ddde18e00bfd
oai_identifier_str oai:ri.conicet.gov.ar:11336/21115
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutationsMaarouf, Chera L.Daugs, Ian D.Spina, SalvatoreVidal, RubenKokjohn, Tyler A.Patton, R. LyleKalback, Walter M.Luehrs, Dean C.Walker, Douglas G.Castaño, Eduardo MiguelBeach, Thomas G.Ghetti, BernardinoRoher, Alex E.presenilinFADmutationshttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1BACKGROUND: Mutations in the presenilin (PSEN) genes are associated with early-onset familial Alzheimer's disease (FAD). Biochemical characterizations and comparisons have revealed that many PSEN mutations alter gamma-secretase activity to promote accumulation of toxic Abeta42 peptides. In this study, we compared the histopathologic and biochemical profiles of ten FAD cases expressing independent PSEN mutations and determined the degradation patterns of amyloid-beta precursor protein (AbetaPP), Notch, N-cadherin and Erb-B4 by gamma-secretase. In addition, the levels of Abeta40/42 peptides were quantified by ELISA. RESULTS: We observed a wide variation in type, number and distribution of amyloid deposits and neurofibrillary tangles. Four of the ten cases examined exhibited a substantial enrichment in the relative proportions of Abeta40 over Abeta42. The AbetaPP N-terminal and C-terminal fragments and Tau species, assessed by Western blots and scanning densitometry, also demonstrated a wide variation. The Notch-1 intracellular domain was negligible by Western blotting in seven PSEN cases. There was significant N-cadherin and Erb-B4 peptide heterogeneity among the different PSEN mutations. CONCLUSION: These observations imply that missense mutations in PSEN genes can alter a range of key gamma-secretase activities to produce an array of subtly different biochemical, neuropathological and clinical manifestations. Beyond the broad common features of dementia, plaques and tangles, the various PSEN mutations resulted in a wide heterogeneity and complexity and differed from sporadic AD.Fil: Maarouf, Chera L.. Sun Health Research Institute; Estados UnidosFil: Daugs, Ian D.. Sun Health Research Institute; Estados UnidosFil: Spina, Salvatore. Universita Degli Studi Di Siena; Italia. Indiana University; Estados UnidosFil: Vidal, Ruben. Indiana University; Estados UnidosFil: Kokjohn, Tyler A.. Sun Health Research Institute; Estados Unidos. Midwestern University; 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: Walker, Douglas G.. Sun Health Research Institute; 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: Beach, Thomas G.. Sun Health Research Institute; Estados UnidosFil: Ghetti, Bernardino. Indiana University; Estados UnidosFil: Roher, Alex E.. Sun Health Research Institute; Estados UnidosBioMed Central2008-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/21115Maarouf, Chera L.; Daugs, Ian D.; Spina, Salvatore; Vidal, Ruben; Kokjohn, Tyler A.; et al.; Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations; BioMed Central; Molecular Neurodegeneration; 3; 20; 11-2008; 1-181750-13261750-1326CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/1750-1326-3-20info:eu-repo/semantics/altIdentifier/doi/10.1186/1750-1326-3-20info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:58:32Zoai:ri.conicet.gov.ar:11336/21115instacron: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 09:58:32.757CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations
title Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations
spellingShingle Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations
Maarouf, Chera L.
presenilin
FAD
mutations
title_short Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations
title_full Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations
title_fullStr Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations
title_full_unstemmed Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations
title_sort Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations
dc.creator.none.fl_str_mv Maarouf, Chera L.
Daugs, Ian D.
Spina, Salvatore
Vidal, Ruben
Kokjohn, Tyler A.
Patton, R. Lyle
Kalback, Walter M.
Luehrs, Dean C.
Walker, Douglas G.
Castaño, Eduardo Miguel
Beach, Thomas G.
Ghetti, Bernardino
Roher, Alex E.
author Maarouf, Chera L.
author_facet Maarouf, Chera L.
Daugs, Ian D.
Spina, Salvatore
Vidal, Ruben
Kokjohn, Tyler A.
Patton, R. Lyle
Kalback, Walter M.
Luehrs, Dean C.
Walker, Douglas G.
Castaño, Eduardo Miguel
Beach, Thomas G.
Ghetti, Bernardino
Roher, Alex E.
author_role author
author2 Daugs, Ian D.
Spina, Salvatore
Vidal, Ruben
Kokjohn, Tyler A.
Patton, R. Lyle
Kalback, Walter M.
Luehrs, Dean C.
Walker, Douglas G.
Castaño, Eduardo Miguel
Beach, Thomas G.
Ghetti, Bernardino
Roher, Alex E.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv presenilin
FAD
mutations
topic presenilin
FAD
mutations
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv BACKGROUND: Mutations in the presenilin (PSEN) genes are associated with early-onset familial Alzheimer's disease (FAD). Biochemical characterizations and comparisons have revealed that many PSEN mutations alter gamma-secretase activity to promote accumulation of toxic Abeta42 peptides. In this study, we compared the histopathologic and biochemical profiles of ten FAD cases expressing independent PSEN mutations and determined the degradation patterns of amyloid-beta precursor protein (AbetaPP), Notch, N-cadherin and Erb-B4 by gamma-secretase. In addition, the levels of Abeta40/42 peptides were quantified by ELISA. RESULTS: We observed a wide variation in type, number and distribution of amyloid deposits and neurofibrillary tangles. Four of the ten cases examined exhibited a substantial enrichment in the relative proportions of Abeta40 over Abeta42. The AbetaPP N-terminal and C-terminal fragments and Tau species, assessed by Western blots and scanning densitometry, also demonstrated a wide variation. The Notch-1 intracellular domain was negligible by Western blotting in seven PSEN cases. There was significant N-cadherin and Erb-B4 peptide heterogeneity among the different PSEN mutations. CONCLUSION: These observations imply that missense mutations in PSEN genes can alter a range of key gamma-secretase activities to produce an array of subtly different biochemical, neuropathological and clinical manifestations. Beyond the broad common features of dementia, plaques and tangles, the various PSEN mutations resulted in a wide heterogeneity and complexity and differed from sporadic AD.
Fil: Maarouf, Chera L.. Sun Health Research Institute; Estados Unidos
Fil: Daugs, Ian D.. Sun Health Research Institute; Estados Unidos
Fil: Spina, Salvatore. Universita Degli Studi Di Siena; Italia. Indiana University; Estados Unidos
Fil: Vidal, Ruben. Indiana University; Estados Unidos
Fil: Kokjohn, Tyler A.. Sun Health Research Institute; Estados Unidos. Midwestern University; 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: Walker, Douglas G.. Sun Health Research Institute; 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: Beach, Thomas G.. Sun Health Research Institute; Estados Unidos
Fil: Ghetti, Bernardino. Indiana University; Estados Unidos
Fil: Roher, Alex E.. Sun Health Research Institute; Estados Unidos
description BACKGROUND: Mutations in the presenilin (PSEN) genes are associated with early-onset familial Alzheimer's disease (FAD). Biochemical characterizations and comparisons have revealed that many PSEN mutations alter gamma-secretase activity to promote accumulation of toxic Abeta42 peptides. In this study, we compared the histopathologic and biochemical profiles of ten FAD cases expressing independent PSEN mutations and determined the degradation patterns of amyloid-beta precursor protein (AbetaPP), Notch, N-cadherin and Erb-B4 by gamma-secretase. In addition, the levels of Abeta40/42 peptides were quantified by ELISA. RESULTS: We observed a wide variation in type, number and distribution of amyloid deposits and neurofibrillary tangles. Four of the ten cases examined exhibited a substantial enrichment in the relative proportions of Abeta40 over Abeta42. The AbetaPP N-terminal and C-terminal fragments and Tau species, assessed by Western blots and scanning densitometry, also demonstrated a wide variation. The Notch-1 intracellular domain was negligible by Western blotting in seven PSEN cases. There was significant N-cadherin and Erb-B4 peptide heterogeneity among the different PSEN mutations. CONCLUSION: These observations imply that missense mutations in PSEN genes can alter a range of key gamma-secretase activities to produce an array of subtly different biochemical, neuropathological and clinical manifestations. Beyond the broad common features of dementia, plaques and tangles, the various PSEN mutations resulted in a wide heterogeneity and complexity and differed from sporadic AD.
publishDate 2008
dc.date.none.fl_str_mv 2008-11
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/11336/21115
Maarouf, Chera L.; Daugs, Ian D.; Spina, Salvatore; Vidal, Ruben; Kokjohn, Tyler A.; et al.; Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations; BioMed Central; Molecular Neurodegeneration; 3; 20; 11-2008; 1-18
1750-1326
1750-1326
CONICET Digital
CONICET
url http://hdl.handle.net/11336/21115
identifier_str_mv Maarouf, Chera L.; Daugs, Ian D.; Spina, Salvatore; Vidal, Ruben; Kokjohn, Tyler A.; et al.; Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations; BioMed Central; Molecular Neurodegeneration; 3; 20; 11-2008; 1-18
1750-1326
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://molecularneurodegeneration.biomedcentral.com/articles/10.1186/1750-1326-3-20
info:eu-repo/semantics/altIdentifier/doi/10.1186/1750-1326-3-20
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 BioMed Central
publisher.none.fl_str_mv BioMed Central
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
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score 13.070432

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