Aβ42 production in brain capillary endothelial cells after oxygen and glucose deprivation.

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.