TY - JOUR
T1 - Aβ42 production in brain capillary endothelial cells after oxygen and glucose deprivation
AU - Bulbarelli, Alessandra
AU - Lonati, Elena
AU - Brambilla, Anna
AU - Orlando, Antonina
AU - Cazzaniga, Emanuela
AU - Piazza, Fabrizio
AU - Ferrarese, Carlo
AU - Masserini, Massimo
AU - Sancini, Giulio
PY - 2012/4
Y1 - 2012/4
N2 - Although the diverse triggers of AD are still under debate, the hypothesis of the contribution of cerebrovascular deficiencies has emerged in recent years. Cerebrovascular dysfunction may precede cognitive decline and onset of neurodegeneration. Indeed, the toxic Aβ 42 aggregates constituting senile plaques, one of AD hallmarks, is often detected as amorphous material or fine fibrils in the brain capillary of AD patients. Aβ 42 causing cerebral microangiopathy might originate either from the circulating blood, the vessel wall itself or the brain parenchyma. In the present investigation we show, for the first time, that in rat brain capillary endothelial cells (RBE4), in vitro oxygen glucose deprivation treatment elicits 250% of Aβ 42 peptide production increase through a mechanism that involves the hypoxia inducible factor-1-mediated β-secretase (BACE1) up-regulation. Furthermore, we observed a time dependent increase of amyloid protein precursor (AβPP) gene and protein expression, confirming previous reports which established the existence of AβPP in the cerebrovascular domain.Our experimental evidences point out that ischemic events may directly contribute in brain capillary endothelial cells to the enhancement of the amyloidogenic metabolism, leading to intracellular deposition of Aβ 42. This events may contribute to the impairment of Aβ brain clearance and AD related blood brain barrier dysfunctions.
AB - Although the diverse triggers of AD are still under debate, the hypothesis of the contribution of cerebrovascular deficiencies has emerged in recent years. Cerebrovascular dysfunction may precede cognitive decline and onset of neurodegeneration. Indeed, the toxic Aβ 42 aggregates constituting senile plaques, one of AD hallmarks, is often detected as amorphous material or fine fibrils in the brain capillary of AD patients. Aβ 42 causing cerebral microangiopathy might originate either from the circulating blood, the vessel wall itself or the brain parenchyma. In the present investigation we show, for the first time, that in rat brain capillary endothelial cells (RBE4), in vitro oxygen glucose deprivation treatment elicits 250% of Aβ 42 peptide production increase through a mechanism that involves the hypoxia inducible factor-1-mediated β-secretase (BACE1) up-regulation. Furthermore, we observed a time dependent increase of amyloid protein precursor (AβPP) gene and protein expression, confirming previous reports which established the existence of AβPP in the cerebrovascular domain.Our experimental evidences point out that ischemic events may directly contribute in brain capillary endothelial cells to the enhancement of the amyloidogenic metabolism, leading to intracellular deposition of Aβ 42. This events may contribute to the impairment of Aβ brain clearance and AD related blood brain barrier dysfunctions.
KW - Alzheimer's disease
KW - Amyloid-β 1-42
KW - Amyloid-β protein precursor
KW - Blood brain barrier
KW - Brain ischemia-anoxia
KW - HIF-1alpha protein
UR - http://www.scopus.com/inward/record.url?scp=84858744141&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84858744141&partnerID=8YFLogxK
U2 - 10.1016/j.mcn.2012.01.007
DO - 10.1016/j.mcn.2012.01.007
M3 - Article
C2 - 22326856
AN - SCOPUS:84858744141
VL - 49
SP - 415
EP - 422
JO - Molecular and Cellular Neurosciences
JF - Molecular and Cellular Neurosciences
SN - 1044-7431
IS - 4
ER -