HTRA2/Omi Antibody MAB1458 from R&D Systems, a Bio-Techne Brand

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Molecular Neurobiology
July 01 2019

Fig 1: Hypothetical pathway linking the mitochondrial function, OMI/HTRA2, apoptosis, and intracellular cholinergic signaling. The well-documented presence of nicotinic acetylcholine receptors (nAChRs) at the mitochondrial outer membrane defines all eukaryotic cells as cholinoceptive cells and acetylcholine, the main known endogenous ligand of these receptors, as a universal intracellular signaling molecule. (1) As a matter of fact, biosynthesis of ACh is directly linked to mitochondrial glycolysis and citric acid cycle. In mitochondria, glucose converted to pyruvate, and thereby production of acetyl-Coenzyme A (A-CoA) [41], (2) which is partly used in the citric acid cycle for generation of bioenergetic molecules such as ATP, and (3) the rest may enter into the cytoplasm for instance for biosynthesis of ACh by ChAT, which is apparently required for activation of the mitochondrial nAChR (mt-nAChR). (4) The mt-nAChRs and their regular activation by intracellular ACh may hence function as a biodynamic sensor. For instance, in favorable conditions, a high access to glucose is sensed due to production of ACh and activation of mt-nAChRs, (5) thereby preventing auto processing of the mitochondrial serine protease OMI/HTRA2, (6) which could otherwise lead to activation of intrinsic mitochondrial apoptotic pathway [39, 42]. Certain conditions, such as ongoing pathological processes (like those occurring in the AD brain) or other stressful stimuli, may either cause mitochondrial dysfunction and/or greatly limit mitochondrial access to glucose and production of pyruvate, leading to diminished synthesis of A-CoA and thereby ACh. Indeed, there are direct links between ACh and insulin secretion [43], and/or insulin resistance and Alzheimer’s disease [44], glucose metabolism [45], as well as mitochondrial dysfunction [46]. In such circumstances, a hypothetical pathway is that as a mean to maintain protective action of ACh through mt-nAChRs [39, 42], the reduced cytosolic A-CoA induces (7) translocation of ChAT into the cell nucleus, where ChAT somehow will participate in modulation of gene expression of various key proteins [47]. (8) Two of these key proteins are most likely nAChR and ChAT itself. This could explain the positive correlation between OMI/HTRA2, nAChR, and ChAT reported in the current study (Figs. 4 and 5). In other words, an increase in the nAChR levels will enhance the possibility of activation of the receptors even at reduced levels of intracellular ACh, while an increase in ChAT levels could reflect an attempt to increase ACh biosynthesis. This may work if the cause is not a reduced access to pyruvate, and thereby a severe depletion of A-CoA, but rather excessive degradation of ACh. This latter scenario may be caused, for instance, by certain stress stimuli, known to shift the ACHE gene transcription in favor of the soluble stress-associated read-through AChE splice variant (AChE-R) [48–50], which could result in excessive degradation of the intracellular ACh. The observed positive correlation between OMI/HTRA2 and the stress-associated AChE-R variant support this latter notion. However, when such preventive measures (totally or partially) fail to normalize the intracellular ACh-signaling, OMI/HTRA2 mitochondrial serine protease (perhaps together with cytochrome C) is expected to be released into the cytoplasm, initiating apoptosis cascades [6]. This explains our finding of higher levels of activated OMI/HTRA2, and its cytoplasmic dispersion in the AD brain compared to control (Fig. 1). The association of OMI/HTRA2 with BuChE may be related to the same phenomenon occurring in non-neuronal cells, such as astrocytes, in which the intracellular BuChE may replace the AChE-R variant since BuChE in the brain is known to have mainly astroglial origin
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Molecular Neurobiology
July 01 2019

Fig 2: Positive correlation of activated OMI/HTRA2 with BuChE protein expression and activity. a–d Graphs showing the positive correlation of OMI/HTRA2 with s-BuChE (a, b) and i-BuChE (c, d) protein expression in the average of the three analyzed brain regions (a, c) and in the MFG region (b, d). e–h Graphs showing the positive correlation of OMI/HTRA2 with s-BuChE (e, f) and m-BuChE (g, h) protein activity in the average of the three analyzed brain regions (e, g) and in the MFG region (f, h). BuChE = butyrylcholinesterase. BuChE protein expression and activity were quantified in the brain tissue extract from AD (n = 6) and non-demented controls (n = 6). Postmortem brain tissues were from medial frontal gyrus (MFG), superior temporalis gyrus (STG), and superior parietal gyrus (SPG) regions. s-, m-, and i- refer to amount of BuChE quantified in the soluble (s-), ionic (i-), and membrane-bound (m-) protein extracts from each of the brain tissues and regions as described in the “Materials and Methods” section
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Molecular Neurobiology
July 01 2019

Fig 3: OMI/HTRA2 protein level is higher in AD than control brains. a, b Immunohistochemical detection of OMI/HTRA2 in human postmortem brain sections of frontal cortex. Representative image of sections from non-demented controls (a) and AD (b) subjects. Staining: OMI/HTRA2 (brown): anti-OMI/HTRA2 rabbit primary antibody, biotinylated horse anti-rabbit antibody, and ABC-Elite HRP. Counterstaining: hematoxylin (blue). Scale bar = 20 µm. c Quantitative analyses showing the number of cells that present either a diffuse or punctuate staining pattern of OMI/HTRA2 in postmortem brain tissues. d, e Quantification of activated OMI/HTRA2 protein levels in postmortem brain homogenates (BH) of AD subjects (n = 6) and non-demented controls (n = 6), by sandwich ELISA. d Box plot graph showing the overall level of activated OMI/HTRA2 in AD compared to controls, measured in all the extracts from the three brain regions and expressed as ng/mg of total protein. e Graph showing the level of activated OMI/HTRA2 in each brain region separately, expressed as percentage of the control levels. f, gOMI/HTRA2 gene expression was quantified in the postmortem brain samples from the MFG, SPG, and STG brain regions. f Graph showing the normalized transcript levels of OMI/HTRA2 in each of the analyzed brain regions. g Negative correlation of OMI/HTRA2 transcript levels and activated OMI/HTRA2 protein levels, expressed as % of the mean of the controls (Ctrl). Activated OMI/HTRA2 was quantified in medial frontal gyrus (MFG), superior temporalis gyrus (STG), and superior parietal gyrus (SPG) brain regions. The total activated OMI/HTRA2 refers to the sum of its protein levels in all extracts. AD, dark gray squares; non-demented controls, light gray squares. Mean values ± S.E.M. are shown (two asterisks, p < 0.01; one asterisk, p < 0.05)
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Molecular Neurobiology
July 01 2019

Fig 4: Positive correlation between OMI/HTRA2 and neurotrophic factors at both the gene expression and protein levels. OMI/HTRA2, NGF, and BDNF gene expression and protein levels were quantified in AD subjects’ (n = 6) and non-demented controls’ (n = 6) postmortem brain, in medial frontal gyrus (MFG), superior temporalis gyrus (STG), and superior parietal gyrus (SPG) brain regions. a–d Graphs showing the positive correlation between OMI/HTRA2 gene expression and NGF gene expression, in the average of the three analyzed brain regions (a) and in each region separately (b–d). e Graph showing the positive correlation between s-NGF and activated OMI/HTRA2 protein levels in the SPG region. f–i Graphs showing the positive correlation between OMI/HTRA2 gene expression and BDNF gene expression, in the average of the three analyzed brain regions (f) and in each region separately (g–i). NGF = nerve growth factor, BDNF = brain-derived neurotrophic factor, s-NGF = amount of NGF measured in the soluble brain extract
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Molecular Neurobiology
July 01 2019

Fig 5: Positive correlation between OMI/HTRA2 and CHRNA7 gene expression. OMI/HTRA2 and CHRNA7 gene expression were quantified in AD subjects’ (n = 6) and non-demented controls’ (n = 6) postmortem brain, in medial frontal gyrus (MFG), superior temporalis gyrus (STG), and superior parietal gyrus (SPG) brain regions. a–d Graphs showing the positive correlation between OMI/HTRA2 gene expression and CHRNA7 gene expression, in the average of the three analyzed brain regions (a) and in each region separately (b–d). AD, dark gray squares; non-demented controls, light gray squares. CHRNA7 = a7 nicotinic acetylcholine receptor gene

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HTRA2/Omi Antibody

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The HTRA2/Omi Antibody from R&D Systems, a Bio-Techne Brand is a Mouse Monoclonal antibody to HTRA2. This antibody recognizes Homo Sapiens, and Human antigen. The HTRA2/Omi Antibody has been validated for the following applications: Immunocytochemistry, and Western Blot.

Molecular Neurobiology

Molecular Neurobiology

Molecular Neurobiology

Molecular Neurobiology

Molecular Neurobiology

HTRA2/Omi Antibody from R&D Systems, a Bio-Techne Brand

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R&D Systems, a Bio-Techne Brand

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HTRA2/Omi Antibody from R&D Systems, a Bio-Techne Brand

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