Increased Active OMI/HTRA2 Serine Protease Displays a Positive Correlation with Cholinergic Alterations in the Alzheimer's Disease Brain

被引:26
|
作者
Darreh-Shori, Taher [1 ]
Rezaeianyazdi, Sareh [2 ]
Lana, Erica [1 ]
Mitra, Sumonto [1 ]
Gellerbring, Anna [1 ]
Karami, Azadeh [1 ]
Bogdanovic, Nenad [2 ,3 ]
Lithner, Christina Unger [1 ]
Winblad, Bengt [2 ]
Behbahani, Homira [2 ]
机构
[1] Karolinska Inst, NVS Dept, Ctr Alzheimer Res, Div Clin Geriatr, Neo7th Floor, S-14183 Huddinge, Sweden
[2] Karolinska Inst, NVS Dept, Ctr Alzheimer Res, Div Neurogeriatr, S-14183 Huddinge, Sweden
[3] Karolinska Univ Hosp, Neurogeriatr Clin, Ctr Alzheimer Res, NVS Dept,Karolinska Inst, Stockholm, Sweden
基金
瑞典研究理事会;
关键词
Alzheimer's disease; OMI/HTRA2; Cholinergicmarkers; NGF; APP; alpha 7 nicotinic acetylcholine receptor; AMYLOID PRECURSOR PROTEIN; READTHROUGH ACETYLCHOLINESTERASE; NEUROPROTECTIVE ROLE; BASAL FOREBRAIN; APP METABOLISM; HUMAN HTRA2; APOPTOSIS; STRESS; EXPRESSION; INHIBITOR;
D O I
10.1007/s12035-018-1383-3
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
HTRA2 (high-temperature requirement serine protease A2) is a mitochondrial serine protease involved in several cellular processes, including autophagy, chaperone activity, and apoptosis. Few studies on the role of OMI/HTRA2 in Alzheimer's disease (AD) are available, but none on its relationship with the cholinergic system and neurotrophic factors as well as other AD-related proteins. In this study, immunohistochemical analyses revealed that AD patients had a higher cytosolic distribution of OMI/HTRA2 protein compared to controls. Quantitative analyses on brain extracts indicated a significant increase in the active form of OMI/HTRA2 in the AD brain. Activated OMI/HTRA2 protein positively correlated with stress-associated read-through acetylcholinesterase activity. In addition, alpha 7 nicotinic acetylcholine receptor gene expression, a receptor also known to be localized on the outer membrane of mitochondria, showed a strong correlation with OMI/HTRA2 gene expression in three different brain regions. Interestingly, the activated OMI/HTRA2 levels also correlated with the activity of the acetylcholinebiosynthesizing enzyme, choline acetyltransferase (ChAT); with levels of the neurotrophic factors, NGF and BDNF; with levels of the soluble fragments of amyloid precursor protein (APP); and with gene expression of the microtubule-associated protein tau in the examined brain regions. Overall, the results demonstrate increased levels of the mitochondrial serine protease OMI/ HTRA2, and a coherent pattern of association between the activated form of OMI/HTRA2 and several key proteins involved in AD pathology. In this paper, we propose a new hypothetical model to highlight the importance and needs of further investigation on the role of OMI/HTRA2 in the mitochondrial function and AD.
引用
收藏
页码:4601 / 4619
页数:19
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