TY - JOUR
T1 - Antisense directed against PS-1 gene decreases brain oxidative markers in aged senescence accelerated mice (SAMP8) and reverses learning and memory impairment
T2 - A proteomics study
AU - Fiorini, Ada
AU - Sultana, Rukhsana
AU - Förster, Sarah
AU - Perluigi, Marzia
AU - Cenini, Giovanna
AU - Cini, Chiara
AU - Cai, Jian
AU - Klein, Jon B.
AU - Farr, Susan A.
AU - Niehoff, Michael L.
AU - Morley, John E.
AU - Kumar, Vijaya B.
AU - Allan Butterfield, D.
N1 - Funding Information:
This work was supported in part by a NIH grant to D.A.B. [ AG-05119 ].
PY - 2013
Y1 - 2013
N2 - Amyloid β-peptide (Aβ) plays a central role in the pathophysiology of Alzheimer's disease (AD) through the induction of oxidative stress. This peptide is produced by proteolytic cleavage of amyloid precursor protein (APP) by the action of β- and γ-secretases. Previous studies demonstrated that reduction of Aβ, using an antisense oligonucleotide (AO) directed against the Aβ region of APP, reduced oxidative stress-mediated damage and prevented or reverted cognitive deficits in senescence-accelerated prone mice (SAMP8), a useful animal model for investigating the events related to Aβ pathology and possibly to the early phase of AD. In the current study, aged SAMP8 were treated by AO directed against PS-1, a component of the γ-secretase complex, and tested for learning and memory in T-maze foot shock avoidance and novel object recognition. Brain tissue was collected to identify the decrease of oxidative stress and to evaluate the proteins that are differently expressed and oxidized after the reduction in free radical levels induced by Aβ. We used both expression proteomics and redox proteomics approaches. In brain of AO-treated mice a decrease of oxidative stress markers was found, and the proteins identified by proteomics as expressed differently or nitrated are involved in processes known to be impaired in AD. Our results suggest that the treatment with AO directed against PS-1 in old SAMP8 mice reverses learning and memory deficits and reduces Aβ-mediated oxidative stress with restoration to the normal condition and identifies possible pharmacological targets to combat this devastating dementing disease.
AB - Amyloid β-peptide (Aβ) plays a central role in the pathophysiology of Alzheimer's disease (AD) through the induction of oxidative stress. This peptide is produced by proteolytic cleavage of amyloid precursor protein (APP) by the action of β- and γ-secretases. Previous studies demonstrated that reduction of Aβ, using an antisense oligonucleotide (AO) directed against the Aβ region of APP, reduced oxidative stress-mediated damage and prevented or reverted cognitive deficits in senescence-accelerated prone mice (SAMP8), a useful animal model for investigating the events related to Aβ pathology and possibly to the early phase of AD. In the current study, aged SAMP8 were treated by AO directed against PS-1, a component of the γ-secretase complex, and tested for learning and memory in T-maze foot shock avoidance and novel object recognition. Brain tissue was collected to identify the decrease of oxidative stress and to evaluate the proteins that are differently expressed and oxidized after the reduction in free radical levels induced by Aβ. We used both expression proteomics and redox proteomics approaches. In brain of AO-treated mice a decrease of oxidative stress markers was found, and the proteins identified by proteomics as expressed differently or nitrated are involved in processes known to be impaired in AD. Our results suggest that the treatment with AO directed against PS-1 in old SAMP8 mice reverses learning and memory deficits and reduces Aβ-mediated oxidative stress with restoration to the normal condition and identifies possible pharmacological targets to combat this devastating dementing disease.
KW - Alzheimer's disease
KW - Amyloid precursor protein
KW - Amyloid β-peptide
KW - Senescence accelerated mouse
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U2 - 10.1016/j.freeradbiomed.2013.06.017
DO - 10.1016/j.freeradbiomed.2013.06.017
M3 - Article
C2 - 23777706
AN - SCOPUS:84880181659
SN - 0891-5849
VL - 65
SP - 1
EP - 14
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -