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

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• 作者：Anna Brambilla^a ; ^{anna.brambilla@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Elena Lonati^a ; ^{elena.lonati1@unimib.it" class="auth_mail" title="E-mail the corresponding author} ; Chiara Milani^a ; ^{c.milani8@campus.unimib.it" class="auth_mail" title="E-mail the corresponding author} ; Angela Maria Rizzo^b ; ^{angelamaria.rizzo@unimi.it" class="auth_mail" title="E-mail the corresponding author} ; Francesca Farina^a ; ^{francesca.farina1@unimib.it" class="auth_mail" title="E-mail the corresponding author} ; Laura Botto^a ; ^{laura.botto@unimib.it" class="auth_mail" title="E-mail the corresponding author} ; Massimo Masserini^a ; ^{massimo.masserini@unimib.it" class="auth_mail" title="E-mail the corresponding author} ; Paola Palestini^a ; ^{paola.palestini@unimib.it" class="auth_mail" title="E-mail the corresponding author} ; Alessandra Bulbarelli^a ; ^{alessandra.bulbarelli@unimib.it" class="auth_mail" title="E-mail the corresponding author}
• 关键词：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
• 刊名：International Journal of Biochemistry and Cell Biology
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：69
• 期：Complete
• 页码：95-104
• 全文大小：1728 K

文摘

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.