Is cholesterol and amyloid-β stress induced CD147 expression a protective response? Evidence that extracellular cyclophilin a mediated neuroprotection is reliant on CD147.
The CD147 protein is a ubiquitous multifunctional membrane receptor. Expression of CD147, which is regulated by sterol carrier protein, reportedly modulates amyloid-β (Aβ), 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 Aβ can alter CD147 expression in rat cortical neuronal cultures. Water-soluble cholesterol and Aβ42 dose-dependently increased CD147 protein expression, but reduced FL-AβPP protein expression. Cholesterol and Aβ42 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 Aβ42 exposure. We showed that increased CD147 expression protected against Aβ42, only when rCYPA protein was added to neuronal cultures. Together, our findings reveal potentially important relationships between cholesterol loading, CD147 expression, Aβ toxicity, and the putative involvement of CYPA protein in neuroprotection in AD.
Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Australian Neuro-Muscular Research Institute, Nedlands, WA, Australia Centre of Excellence for Alzheimer's disease Research and Care, School of Medical Sciences, Edith Cowan University, Joondalup, Australia Sir James McCusker Alzheimer's Disease Research Unit, Hollywood Private Hospital, Nedlands, WA, Australia.
Limbikani J
LJ
Kanyenda
Centre of Excellence for Alzheimer's disease Research and Care, School of Medical Sciences, Edith Cowan University, Joondalup, Australia Sir James McCusker Alzheimer's Disease Research Unit, Hollywood Private Hospital, Nedlands, WA, Australia School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, WA, Australia School of Public Health, Curtin University, Bentley, WA, Australia Co-operative Research Centre (CRC) for Mental Health, http://www.mentalhealthcrc.com, Australia.
Guiseppe
G
Verdile
Centre of Excellence for Alzheimer's disease Research and Care, School of Medical Sciences, Edith Cowan University, Joondalup, Australia Sir James McCusker Alzheimer's Disease Research Unit, Hollywood Private Hospital, Nedlands, WA, Australia School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, WA, Australia School of Public Health, Curtin University, Bentley, WA, Australia.
Ralph
R
Martins
Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Australian Neuro-Muscular Research Institute, Nedlands, WA, Australia Department of Neurosurgery, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
Bruno P
BP
Meloni
Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Australian Neuro-Muscular Research Institute, Nedlands, WA, Australia.
Joanne
J
Chieng
Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Australian Neuro-Muscular Research Institute, Nedlands, WA, Australia.
Francis
F
Mastaglia
Centre of Excellence for Alzheimer's disease Research and Care, School of Medical Sciences, Edith Cowan University, Joondalup, Australia Sir James McCusker Alzheimer's Disease Research Unit, Hollywood Private Hospital, Nedlands, WA, Australia Co-operative Research Centre (CRC) for Mental Health, http://www.mentalhealthcrc.com, Australia.
Simon M
SM
Laws
Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Australian Neuro-Muscular Research Institute, Nedlands, WA, Australia.
Ryan S
RS
Anderton
Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Australian Neuro-Muscular Research Institute, Nedlands, WA, Australia.
Sherif
S
Boulos
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051926:Basigin / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002784:Cholesterol / Q000494:pharmacology*; D021984:Cyclophilin A / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014161:Transduction, Genetic
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D051926:Basigin; D049452:Green Fluorescent Proteins; D002784:Cholesterol; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D021984:Cyclophilin A
Alzheimer's disease; Aβ$_{42}$; CD147; cholesterol; cyclophilin A; neuroprotection