Loss of RBPj in postnatal excitatory neurons does not cause neurodegeneration or memory impairments in aged mice.

Previous studies suggest that loss of γ-secretase activity in postnatal mouse brains causes age-dependent memory impairment and neurodegeneration. Due to the diverse array of γ-secretase substrates, it remains to be demonstrated whether loss of cleavage of any specific substrate(s) is responsible fo...

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Autores principales:	Chihiro Sato, Mustafa Turkoz, Joshua T Dearborn, David F Wozniak, Raphael Kopan, Matthew R Hass
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/866e48f701074e758bca789c28719da6
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spelling	oai:doaj.org-article:866e48f701074e758bca789c28719da62021-11-18T08:10:51ZLoss of RBPj in postnatal excitatory neurons does not cause neurodegeneration or memory impairments in aged mice.1932-620310.1371/journal.pone.0048180https://doaj.org/article/866e48f701074e758bca789c28719da62012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23110206/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Previous studies suggest that loss of γ-secretase activity in postnatal mouse brains causes age-dependent memory impairment and neurodegeneration. Due to the diverse array of γ-secretase substrates, it remains to be demonstrated whether loss of cleavage of any specific substrate(s) is responsible for these defects. The bulk of the phenotypes observed in mammals deficient for γ-secretase or exposed to γ-secretase inhibitors are caused by the loss of Notch receptor proteolysis. Accordingly, inhibition of Notch signaling is the main cause for untoward effects for γ-secretase inhibitors as therapeutics for Alzheimer's disease. Therefore, we wished to determine if loss of canonical Notch signaling is responsible for the age-dependent neurodegeneration observed upon γ-secrectase deficiency in the mouse brain. We generated postnatal forebrain-specific RBPj conditional knockout (cKO) mice using the CamKII-Cre driver and examined behavior and brain pathology in 12-18 month old animals. Since all four mammalian Notch receptor homologues signal via this DNA binding protein, these mice lack canonical Notch signaling. We found that loss of RBPj in mature excitatory neurons was well tolerated, with no evidence for neurodegeneration or of learning and memory impairment in mice aged up to 18 months. The only phenotypic deficit we observed in the RBPj-deficient mice was a subtle abnormality in olfactory preferences, particularly in females. We conclude that the loss of canonical Notch signaling through the four receptors is not responsible for age-dependent neurodegeneration or learning and memory deficits seen in γ-secretase deficient mice.Chihiro SatoMustafa TurkozJoshua T DearbornDavid F WozniakRaphael KopanMatthew R HassPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 10, p e48180 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Chihiro Sato Mustafa Turkoz Joshua T Dearborn David F Wozniak Raphael Kopan Matthew R Hass Loss of RBPj in postnatal excitatory neurons does not cause neurodegeneration or memory impairments in aged mice.
description	Previous studies suggest that loss of γ-secretase activity in postnatal mouse brains causes age-dependent memory impairment and neurodegeneration. Due to the diverse array of γ-secretase substrates, it remains to be demonstrated whether loss of cleavage of any specific substrate(s) is responsible for these defects. The bulk of the phenotypes observed in mammals deficient for γ-secretase or exposed to γ-secretase inhibitors are caused by the loss of Notch receptor proteolysis. Accordingly, inhibition of Notch signaling is the main cause for untoward effects for γ-secretase inhibitors as therapeutics for Alzheimer's disease. Therefore, we wished to determine if loss of canonical Notch signaling is responsible for the age-dependent neurodegeneration observed upon γ-secrectase deficiency in the mouse brain. We generated postnatal forebrain-specific RBPj conditional knockout (cKO) mice using the CamKII-Cre driver and examined behavior and brain pathology in 12-18 month old animals. Since all four mammalian Notch receptor homologues signal via this DNA binding protein, these mice lack canonical Notch signaling. We found that loss of RBPj in mature excitatory neurons was well tolerated, with no evidence for neurodegeneration or of learning and memory impairment in mice aged up to 18 months. The only phenotypic deficit we observed in the RBPj-deficient mice was a subtle abnormality in olfactory preferences, particularly in females. We conclude that the loss of canonical Notch signaling through the four receptors is not responsible for age-dependent neurodegeneration or learning and memory deficits seen in γ-secretase deficient mice.
format	article
author	Chihiro Sato Mustafa Turkoz Joshua T Dearborn David F Wozniak Raphael Kopan Matthew R Hass
author_facet	Chihiro Sato Mustafa Turkoz Joshua T Dearborn David F Wozniak Raphael Kopan Matthew R Hass
author_sort	Chihiro Sato
title	Loss of RBPj in postnatal excitatory neurons does not cause neurodegeneration or memory impairments in aged mice.
title_short	Loss of RBPj in postnatal excitatory neurons does not cause neurodegeneration or memory impairments in aged mice.
title_full	Loss of RBPj in postnatal excitatory neurons does not cause neurodegeneration or memory impairments in aged mice.
title_fullStr	Loss of RBPj in postnatal excitatory neurons does not cause neurodegeneration or memory impairments in aged mice.
title_full_unstemmed	Loss of RBPj in postnatal excitatory neurons does not cause neurodegeneration or memory impairments in aged mice.
title_sort	loss of rbpj in postnatal excitatory neurons does not cause neurodegeneration or memory impairments in aged mice.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/866e48f701074e758bca789c28719da6
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Loss of RBPj in postnatal excitatory neurons does not cause neurodegeneration or memory impairments in aged mice.

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