Network-driven proteogenomics unveils an aging-related imbalance in the olfactory IκBα-NFκB p65 complex functionality in Tg2576 Alzheimer’s disease mouse model
Fecha
2017Autor
Versión
Acceso abierto / Sarbide irekia
Tipo
Artículo / Artikulua
Versión
Versión publicada / Argitaratu den bertsioa
Impacto
|
10.3390/ijms18112260
Resumen
Olfaction is often deregulated in Alzheimer’s disease (AD) patients, and is also impaired
in transgenic Tg2576 AD mice, which overexpress the Swedish mutated form of human amyloid
precursor protein (APP). However, little is known about the molecular mechanisms that accompany
the neurodegeneration of olfactory structures in aged Tg2576 mice. For that, we have applied
proteome- and transcriptom ...
[++]
Olfaction is often deregulated in Alzheimer’s disease (AD) patients, and is also impaired
in transgenic Tg2576 AD mice, which overexpress the Swedish mutated form of human amyloid
precursor protein (APP). However, little is known about the molecular mechanisms that accompany
the neurodegeneration of olfactory structures in aged Tg2576 mice. For that, we have applied
proteome- and transcriptome-wide approaches to probe molecular disturbances in the olfactory
bulb (OB) dissected from aged Tg2576 mice (18 months of age) as compared to those of age
matched wild-type (WT) littermates. Some over-represented biological functions were directly
relevant to neuronal homeostasis and processes of learning, cognition, and behavior. In addition
to the modulation of CAMP responsive element binding protein 1 (CREB1) and APP interactomes,
an imbalance in the functionality of the IκBα-NFκB p65 complex was observed during the aging
process in the OB of Tg2576 mice. At two months of age, the phosphorylated isoforms of olfactory
IκBα and NFκB p65 were inversely regulated in transgenic mice. However, both phosphorylated
proteins were increased at 6 months of age, while a specific drop in IκBα levels was detected in
18-month-old Tg2576 mice, suggesting a transient activation of NFκB in the OB of Tg2576 mice. Taken
together, our data provide a metabolic map of olfactory alterations in aged Tg2576 mice, reflecting the
progressive effect of APP overproduction and β-amyloid (Aβ) accumulation on the OB homeostasis
in aged stages. [--]
Materias
Tg2576 mice,
Olfactory bulb,
Proteogenomics,
Mass-spectrometry
Editor
MDPI
Publicado en
International Journal of Molecular Sciences, 2017, 18, 2260
Departamento
Universidad Pública de Navarra. Departamento de Ciencias de la Salud /
Nafarroako Unibertsitate Publikoa. Osasun Zientziak Saila
Versión del editor
Entidades Financiadoras
This work was funded by grants from the Spanish Ministry of Economy and Competitiveness
(MINECO) (Ref. SAF2014-59340-R), Department of Economic Development from Government of Navarra
(Ref. PC023-24) and Obra Social la Caixa to Enrique Santamaría. Andrea González-Morales and Karina Ausín
were supported by PEJ-2014-A-61949 and PEJ-2014-A-72151 (MINECO). Mercedes Lachén-Montes is supported
by a predoctoral fellowship from the Public University of Navarra (UPNA). The Proteomics Unit of Navarrabiomed is a member of Proteored, PRB2-ISCIII, and is supported by grant
PT13/0001, of the PE I + D + I 2013–2016 funded by ISCIII and FEDER.