Affiliations: [a] Department of Pathology, New York University School of Medicine, New York, NY, USA | [b] Department of Psychiatry, New York University School of Medicine, New York, NY, USA
Correspondence:
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Correspondence to: Jorge A. Ghiso, PhD, New York University School of Medicine, 560 First Avenue, MSB Room 556, New York, NY 10016, USA. Tel.: +1 212 263 7997; Fax: +1 212 263 0858; E-mail: [email protected].
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.
