Ischemic conditions and β-secretase activation: The impact of membrane cholesterol enrichment as triggering factor in rat brain endothelial cells. (December 2015)

• Record Type: Journal Article
• Authors: Brambilla, Anna; Lonati, Elena; Milani, Chiara; Rizzo, Angela Maria; Farina, Francesca; Botto, Laura; Masserini, Massimo; Palestini, Paola; Bulbarelli, Alessandra
• Is Part Of: International journal of biochemistry & cell biology. Volume 69(2015:Dec.)
• Page Start: 95
• Page End: 104
• Publication Date: 2015-12
• Subjects: CNS central nervous system -- AD Alzheimer's disease -- RBE4 rat brain endothelial cell line -- OGD oxygen and glucose deprivation -- ogR oxygen and glucose Restoration -- BACE1 amyloid precursor protein (APP) β-secretase -- PSEN1 presenilin-1 -- Aβ amyloid peptide -- (α-CTF) APP α-carboxyl-terminal fragment -- (β-CTF) APP β-carboxyl-terminal fragment -- HIF1 hypoxia-inducible transcription factor 1 -- β-MCD β-methylcyclodextrin -- PMSF Phenylmethylsulphonyl fluoride -- FBS fetal bovine serum -- BSS balanced salt solution -- MEFs membrane-enriched fraction -- PNS post nuclear supernatant -- TS Triton X-100 soluble fraction -- TI Triton X-100 and insoluble fraction -- OP organic phase -- AP aqueous phase -- DPH 1, 6-diphenyl-1, 2, 5-hexatriene -- ECL enhanced chemiluminescence -- RFU relative fluorescence units -- PL phospholipids -- GG gangliosides -- PE phosphatidylethanolamine -- PS phosphatidylserine -- PI phosphatidylinositol -- PC phosphatidylcholine -- SM sphingomyelin -- Pi phospholipidic phosphorus; Alzheimer's disease -- (AD) -- Brain endothelial cells -- Oxygen glucose deprivation (OGD) -- BACE1 activity -- Amyloid precursor protein (APP) -- Cholesterol; Biochemistry -- Periodicals; Cytology -- Periodicals; Biochemistry -- Periodicals; Cell Biology -- Periodicals; Biochimie -- Périodiques; Cytologie -- Périodiques; Biochimie; Cytologie; Biochemistry; Cytology; Ressource Internet (Descripteur de forme); Périodique électronique (Descripteur de forme); Periodicals; 572.05
• DOI: 10.1016/j.biocel.2015.10.005
• Languages: English
• ISSNs: 1357-2725

Abstract

Abstract: Among harmful conditions damaging the blood–brain barrier, cerebral stroke and reperfusion injuries were proposed as contributing factors to Alzheimer's disease etiology. Indeed it was reported that ischemic conditions promote β-amyloid peptide production in brain endothelial cells, although implicated mechanisms are yet not fully understood. Oxidative injury related to ischemia affects membrane-lipids profile by altering their biochemical properties and structural dynamics, which are also believed to play significant role in the amyloid precursor protein processing, suggesting a link between alterations in lipid membrane composition and β-amyloid peptide production enhancement. Using brain microvascular endothelial cells, here we demonstrate how oxygen and glucose deprivation followed by normal conditions restoration, mimicking ischemic environment, increases cell cholesterol amount (+20%), reduces membrane fluidity and results in strong activation (+40%) of β-secretase 1 enzymatic activity. Moreover, we observed an increase of amyloid precursor protein and β-secretase 1 protein levels with altered localization in non-discrete (Triton X-100 soluble) membrane domains, leading to an enhanced production of amyloid precursor protein β-carboxyl-terminal fragment. Therefore, lipid alterations induced by oxygen and glucose deprivation enhance β-secretase 1 activity, favor its proximity to amyloid precursor protein and may concur to increased amyloidogenic cleavage. The latter, represents a detrimental event that may contribute to β-amyloid homeostasis impairment in the brain and to Alzheimer's disease-related BBB dysfunctions.