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

• Published in: Molecular neurobiology 2019-07, Vol.56 (7), p.4601-4619
• Main Authors: Darreh-Shori, Taher, Rezaeianyazdi, Sareh, Lana, Erica, Mitra, Sumonto, Gellerbring, Anna, Karami, Azadeh, Bogdanovic, Nenad, Lithner, Christina Unger, Winblad, Bengt, Behbahani, Homira
• Format: Article
• Language: English
• Subjects: Acetylcholine - metabolism; Acetylcholinesterase; Acetylcholinesterase - genetics; Acetylcholinesterase - metabolism; Acetyltransferase; Aged; Aged, 80 and over; alpha7 Nicotinic Acetylcholine Receptor - metabolism; Alzheimer Disease - enzymology; Alzheimer's disease; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Apoptosis; Autophagy; Biomarkers - metabolism; Biomedical and Life Sciences; Biomedicine; Brain; Brain - enzymology; Brain - pathology; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - genetics; Brain-Derived Neurotrophic Factor - metabolism; Butyrylcholinesterase - metabolism; Cell Biology; Choline; Choline O-acetyltransferase; Cholinergic transmission; Female; Gene expression; Gene Expression Regulation; High-Temperature Requirement A Serine Peptidase 2 - genetics; High-Temperature Requirement A Serine Peptidase 2 - metabolism; HtrA2 gene; Humans; Male; Medicin och hälsovetenskap; Middle Aged; Mitochondria; Nerve growth factor; Nerve Growth Factor - genetics; Nerve Growth Factor - metabolism; Neurobiology; Neurology; Neurosciences; Neurotrophic factors; Phagocytosis; Proteins; Serine; Serine proteinase; Tau protein; tau Proteins - genetics; tau Proteins - metabolism; Temperature requirements
• ISSN: 0893-7648; 1559-1182; 1559-1182
• DOI: 10.1007/s12035-018-1383-3

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.