Alzheimer disease macrophages shuttle amyloid-beta from neurons to vessels, contributing to amyloid angiopathy.
Neuronal accumulation of oligomeric amyloid-beta (Alphabeta) is considered the proximal cause of neuronal demise in Alzheimer disease (AD) patients. Blood-borne macrophages might reduce Abeta stress to neurons by immigration into the brain and phagocytosis of Alphabeta. We tested migration and export across a blood-brain barrier model, and phagocytosis and clearance of Alphabeta by AD and normal subjects' macrophages. Both AD and normal macrophages were inhibited in Alphabeta export across the blood-brain barrier due to adherence of Abeta-engorged macrophages to the endothelial layer. In comparison to normal subjects' macrophages, AD macrophages ingested and cleared less Alphabeta, and underwent apoptosis upon exposure to soluble, protofibrillar, or fibrillar Alphabeta. Confocal microscopy of stained AD brain sections revealed oligomeric Abeta in neurons and apoptotic macrophages, which surrounded and infiltrated congophilic microvessels, and fibrillar Abeta in plaques and microvessel walls. After incubation with AD brain sections, normal subjects' monocytes intruded into neurons and uploaded oligomeric Abeta. In conclusion, in patients with AD, macrophages appear to shuttle Abeta from neurons to vessels where their apoptosis may release fibrillar Abeta, contributing to cerebral amyloid angiopathy.
Zaghi
Justin
J
Department of Orthopaedic Surgery, UCLA-Orthopaedic Hospital Research Center, Los Angeles, CA 90095-7358, USA.
Goldenson
Ben
B
Inayathullah
Mohammed
M
Lossinsky
Albert S
AS
Masoumi
Ava
A
Avagyan
Hripsime
H
Mahanian
Michelle
M
Bernas
Michael
M
Weinand
Martin
M
Rosenthal
Mark J
MJ
Espinosa-Jeffrey
Araceli
A
de Vellis
Jean
J
Teplow
David B
DB
Fiala
Milan
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D017209:Apoptosis; D001812:Blood-Brain Barrier; D001921:Brain / Q000098:blood supply / Q000473:pathology; D016657:Cerebral Amyloid Angiopathy / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D055806:Microvessels / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D008954:Models, Biological; D009000:Monocytes / Q000502:physiology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010587:Phagocytosis; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
D016229:Amyloid beta-Peptides