1. Increased Active OMI/HTRA2 Serine Protease Displays a Positive Correlation with Cholinergic Alterations in the Alzheimer's Disease Brain.
- Author
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Darreh-Shori T, Rezaeianyazdi S, Lana E, Mitra S, Gellerbring A, Karami A, Bogdanovic N, Lithner CU, Winblad B, and Behbahani H
- Subjects
- Acetylcholinesterase genetics, Acetylcholinesterase metabolism, Aged, Aged, 80 and over, Amyloid beta-Protein Precursor genetics, Amyloid beta-Protein Precursor metabolism, Biomarkers metabolism, Brain pathology, Brain-Derived Neurotrophic Factor genetics, Brain-Derived Neurotrophic Factor metabolism, Butyrylcholinesterase metabolism, Female, Gene Expression Regulation, High-Temperature Requirement A Serine Peptidase 2 genetics, Humans, Male, Middle Aged, Nerve Growth Factor genetics, Nerve Growth Factor metabolism, alpha7 Nicotinic Acetylcholine Receptor metabolism, tau Proteins genetics, tau Proteins metabolism, Acetylcholine metabolism, Alzheimer Disease enzymology, Brain enzymology, High-Temperature Requirement A Serine Peptidase 2 metabolism
- Abstract
OMI/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, α7 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 acetylcholine-biosynthesizing 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.
- Published
- 2019
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