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APP/PS1 transgenic mice overexpressing SREBP2 as a new model to study the pathogenic role of cholesterol in Alzheimer's disease (AD)

AuthorsBarbero-Camps, Elisabet ; Fernández, Anna; Fernández-Checa, José C. ; Colell Riera, Anna
Issue DateJul-2011
CitationAlzheimer's and Dementia 7(4): S517 (2011)
Abstract[Background]: Disruption of cholesterol homeostasis is associated with AD. Increased brain cholesterol triggers amyloid precursor-BACE1 clustering in lipid rafts stimulating the synthesis and aggregation of toxic amyloid beta peptides (Ab). Moreover, we have recently described that the trafficking of cholesterol to mitochondria sensitizes to Ab-mediated neurotoxicity by depletion of mitochondrial glutathione (mGSH). The aims of this work were to examine the regulatory effect of cholesterol in AD progression and to evaluate Ab-induced ER stress as a causal mechanism of the altered cholesterol metabolism in brain. [Methods]: We generated APP/PS1 transgenic mice that overexpress the sterol regulatory element binding protein 2 (Tg-APP/PS1-SREBP2) and analysed several pathological hallmarks of AD at 4, 7 and 10 month of age. [Results]: The increase (1-5-2 fold) of total brain and mitochondrial cholesterol levels and subsequent selective depletion of mGSH were accelerated in Tg-APP/PS1-SREBP2 mice compared to either Tg-APP/PS1 or Tg-SREBP2. Both alterations were detectable in 10-month old Tg-APP/PS1 mice and associated with elevated expression of SREBP2. The incidence of high Ab levels raised with the overexpression of SREBP2 and correlated with enhanced activity of BACE1. Seven-month old Tg-APP/PS1-SREBP2 mice displayed brain oxidative damage and neuroinflammation, features that were unnoticeable in Tg-APP/PS1 mice up to 10 month of age. The increased brain oxidative stress in Tg-APP/PS1-SREBP2 mice promoted the activation of GSK3-beta, ERK1/2 and CDK5 that led to enhanced TAU phosphorilation and neurofibrillary tangle formation. Furthermore, overexpression of SREBP2 accelerated synaptic degeneration and neuronal death. The analyses of GADD153 and GRP78 expression indicated an early onset of ER stress. Moreover, treatment of 10-month old Tg-APP/PS1 mice with the chaperon-like compound sodium 4-phenylbutyrate (4-PBA) significantly reduced the levels of the ER stress markers and prevented the induction of SREBP2 expression as well as the increase of proteins involved in mitochondrial cholesterol transport, including STAR and MLN64. The administration of 4-PBA restored the mitochondrial cholesterol and mGSH content to control levels. [Conclusions]: Increased brain cholesterol by SREBP2 activation potentiates Ab-induced neuronal damage/neurofibrillary tangle formation, accelerating the AD phenotype of Tg-APP/PS1 mice. ER stress and regulation of mitochondrial cholesterol trafficking underlie the pathology progression observed in old Tg-APP/PS1 mice.
DescriptionTrabajo presentado a la Alzheimer's Association 2011 International Conference on Alzheimer's Disease (ICAD 2011) celebrada en Paris del 16 al 21 de julio de 2011.
Identifiersdoi: 10.1016/j.jalz.2011.05.1446
issn: 1552-5260
Appears in Collections:(IIBB) Artículos
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