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.

Brambilla, A., Lonati, E., Milani, C., Rizzo, A.M., Farina, F., Botto, L., et al. (2015). Ischemic conditions and β-secretase activation: The impact of membrane cholesterol enrichment as triggering factor in rat brain endothelial cells. THE INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 69, 95-104 [10.1016/j.biocel.2015.10.005].

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

LONATI, ELENA RITA;MILANI, CHIARA;FARINA, FRANCESCA;BOTTO, LAURA MARIA;MASSERINI, MASSIMO ERNESTO;PALESTINI, PAOLA NOVERINA ADA;BULBARELLI, ALESSANDRA
2015

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.
Articolo in rivista - Articolo scientifico
Scientifica
Ischemia, beta-secretase; cholesterol
English
Brambilla, A., Lonati, E., Milani, C., Rizzo, A.M., Farina, F., Botto, L., et al. (2015). Ischemic conditions and β-secretase activation: The impact of membrane cholesterol enrichment as triggering factor in rat brain endothelial cells. THE INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 69, 95-104 [10.1016/j.biocel.2015.10.005].
Brambilla, A; Lonati, E; Milani, C; Rizzo, A; Farina, F; Botto, L; Masserini, M; Palestini, P; Bulbarelli, A
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/97462
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