ABSTRACT
The CD147 protein is a ubiquitous multifunctional membrane receptor. Expression of CD147, which is regulated by sterol carrier protein, reportedly modulates amyloid-ß (Aß), the neurotoxic peptide implicated in neuronal degeneration in Alzheimer's disease (AD). Given that high fat/cholesterol is linked to amyloid deposition in AD, we investigated if cholesterol and/or Aß can alter CD147 expression in rat cortical neuronal cultures. Water-soluble cholesterol and Aß42 dose-dependently increased CD147 protein expression, but reduced FL-AßPP protein expression. Cholesterol and Aß42 treatment also increased lactate dehydrogenase release but to varying degrees. Upregulation of CD147 expression was probably mediated by oxidative stress, as H2O2 (3 µM) also induced CD147 protein expression in neuronal cultures. In light of these findings, we investigated if CD147 induction was cytoprotective, a compensatory response to injury, or alternatively, a cell death signal. To this end, we used recombinant adenovirus to overexpress human CD147 (in SH-SY5Y cells and primary cortical neurons), and pre-treated cultures with or without recombinant cyclophilin A (rCYPA) protein, prior to Aß42 exposure. We showed that increased CD147 expression protected against Aß42, only when rCYPA protein was added to neuronal cultures. Together, our findings reveal potentially important relationships between cholesterol loading, CD147 expression, Aß toxicity, and the putative involvement of CYPA protein in neuroprotection in AD.
Subject(s)
Amyloid beta-Peptides/pharmacology , Basigin/metabolism , Cholesterol/pharmacology , Cyclophilin A/metabolism , Hydrogen Peroxide/pharmacology , Neurons/drug effects , Peptide Fragments/pharmacology , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Cells, Cultured , Cerebral Cortex/cytology , Cyclophilin A/genetics , Dose-Response Relationship, Drug , Embryo, Mammalian , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Humans , L-Lactate Dehydrogenase/metabolism , Rats , Rats, Sprague-Dawley , Transduction, GeneticABSTRACT
CD147, also known as basigin, EMMPRIN, neurothelin, TCSF, M6, HT7, OX47, or gp42, is a transmembrane glycoprotein of the immunoglobulin super-family. It is expressed in many neuronal and non-neuronal tissues including the hippocampus, pre-frontal cortex thyroid, heart, early erythroid, amygdala, and placenta. This protein is involved in various cellular and biological functions, such as lymphocyte migration and maturation, tissue repair cancer progression, T and B lymphocyte activation, and induction of extracellular matrix metalloproteinase. The CD147 protein interacts with other proteins such as cyclophilin A (CyPA), Cyclophilin B (CyPB), sterol carrier protein (SCP), caveolin-1 and integrins, and can influence amyloid-ß (Aß) peptide levels, a protein that is central to Alzheimer's disease (AD) pathogenesis. Mechanisms by which CD147 regulate Aß levels remain unclear, thus in this review we discuss its involvement in Aß production and clearance and potential mechanisms by which controlling CD147 levels could impact on Aß accumulation and AD pathogenesis.