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

Anna Brambilla, Elena Lonati, Chiara Milani, Angela Maria Rizzo, Francesca Farina, Laura Botto, Massimo Masserini, Paola Palestini, Alessandra Bulbarelli

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)95-104
Number of pages10
JournalInternational Journal of Biochemistry and Cell Biology
Volume69
DOIs
Publication statusPublished - Dec 1 2015

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Keywords

  • Alzheimer's disease(AD)
  • BACE1 activityAmyloid precursor protein (APP)
  • Brain endothelial cells
  • Cholesterol
  • Oxygen glucose deprivation (OGD)

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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