title: Amyloidosis associated with cerebral amyloid angiopathy: cell signaling pathways elicited in cerebral endothelial cells.
abstract: Substantial genetic, biochemical, and in vivo data indicate that progressive accumulation of amyloid-β (Aβ) plays a central role in the pathogenesis of Alzheimer's disease (AD). Historically centered in the importance of parenchymal plaques, the role of cerebral amyloid angiopathy (CAA)--a frequently neglected amyloid deposit present in >80% of AD cases--for the mechanism of disease pathogenesis is now starting to emerge. CAA consistently associates with microvascular modifications, ischemic lesions, micro- and macro-hemorrhages, and dementia, progressively affecting cerebral blood flow, altering blood-brain barrier permeability, interfering with brain clearance mechanisms and triggering a cascade of deleterious pro-inflammatory and metabolic events that compromise the integrity of the neurovascular unit. New evidence highlights the contribution of pre-fibrillar Aβ in the induction of cerebral endothelial cell dysfunction. The recently discovered interaction of oligomeric Aβ species with TRAIL DR4 and DR5 cell surface death receptors mediates the engagement of mitochondrial pathways and sequential activation of multiple caspases, eliciting a cascade of cell death mechanisms while unveiling an opportunity for exploring mechanistic-based therapeutic interventions to preserve the integrity of the neurovascular unit.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY, USA Department of Psychiatry, New York University School of Medicine, New York, NY, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Ghiso
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fossati
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY, USA.
authors.forename: Agueda
authors.initials: A
authors.lastname: Rostagno
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000686:Amyloidosis / Q000150:complications*; D016657:Cerebral Amyloid Angiopathy / Q000150:complications* / Q000473:pathology*; D002540:Cerebral Cortex / Q000473:pathology*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides
keywords: Amyloid-β genetic variants; amyloidosis; cerebral amyloid angiopathy; cerebral microvascular cells; death receptors; familial Alzheimer's disease; inflammation; mitochondrial dysfunction