Alzheimer disease macrophages shuttle amyloid-beta from neurons to vessels, contributing to amyloid angiopathy

Neuronal accumulation of oligomeric amyloid-beta (II2) is considered the proximal cause of neuronal demise in Alzheimer disease (AD) patients. Blood-borne macrophages might reduce A beta stress to neurons by immigration into the brain and phagocytosis of II2. We tested migration and export across a blood-brain barrier model, and phagocytosis and clearance of II2 by AD and normal subjects' macrophages. Both AD and normal macrophages were inhibited in II2 export across the blood-brain barrier due to adherence of A beta-engorged macrophages to the endothelial layer. In comparison to normal subjects' macrophages, AD macrophages ingested and cleared less II2, and underwent apoptosis upon exposure to soluble, protofibrillar, or fibrillar II2. Confocal microscopy of stained AD brain sections revealed oligomeric A beta in neurons and apoptotic macrophages, which surrounded and infiltrated congophilic microvessels, and fibrillar A beta in plaques and microvessel walls. After incubation with AD brain sections, normal subjects' monocytes intruded into neurons and uploaded oligomeric A beta. In conclusion, in patients with AD, macrophages appear to shuttle A beta from neurons to vessels where their apoptosis may release fibrillar A beta, contributing to cerebral amyloid angiopathy.