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

Mol Neurobiol. 2019 Jul;56(7):4601-4619. doi: 10.1007/s12035-018-1383-3. Epub 2018 Oct 25.

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.

Keywords: APP; Alzheimer’s disease; Cholinergic markers; NGF; OMI/HTRA2; α7 nicotinic acetylcholine receptor.

MeSH terms

  • Acetylcholine / metabolism*
  • Acetylcholinesterase / genetics
  • Acetylcholinesterase / metabolism
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / enzymology*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Biomarkers / metabolism
  • Brain / enzymology*
  • 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
  • High-Temperature Requirement A Serine Peptidase 2 / metabolism*
  • Humans
  • Male
  • Middle Aged
  • Nerve Growth Factor / genetics
  • Nerve Growth Factor / metabolism
  • alpha7 Nicotinic Acetylcholine Receptor / metabolism
  • tau Proteins / genetics
  • tau Proteins / metabolism

Substances

  • Amyloid beta-Protein Precursor
  • Biomarkers
  • Brain-Derived Neurotrophic Factor
  • alpha7 Nicotinic Acetylcholine Receptor
  • tau Proteins
  • Nerve Growth Factor
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • High-Temperature Requirement A Serine Peptidase 2
  • Acetylcholine