title: Neuronal zinc exchange with the blood vessel wall promotes cerebral amyloid angiopathy in an animal model of Alzheimer's disease.
abstract: Cerebral amyloid angiopathy (CAA) is common in Alzheimer's disease (AD) and may contribute to dementia and cerebral hemorrhage. Parenchymal beta-amyloid deposition is dependent on the activity of zinc transporter 3 (ZnT3), a neocortical synaptic vesicle membrane protein that causes enrichment of exchangeable Zn2+ in the vesicle, which is externalized on neurotransmission. However, the contribution of zinc to vascular beta-amyloid deposition remains unclear. Here, we identify for the first time an exchangeable pool of Zn2+ in the cerebrovascular wall of normal mice. This histochemically reactive Zn2+ is enriched in CAA in a transgenic mouse model of AD (Tg2576), and a dramatic reduction of CAA occurs after targeted disruption of the Znt3 gene in these mice. Also, in Znt3 knock-out mice, the amount of exchangeable Zn2+ [detected by N-(6-methoxy-8-quinolyl)-p-carboxybenzoylsulphonamide (TFL-Zn)] in the perivascular space was significantly decreased in the neocortex but not in peripheral organs. ZnT3 was not detected in the cerebral vessel walls or in blood components of wild-type mice. Thus, synaptic ZnT3 activity may promote CAA by indirectly raising exchangeable Zn2+ concentrations in the perivascular spaces of the brain.
authors.affiliation: Laboratory for Oxidation Biology, Genetics and Aging Research Unit, Massachusetts General Hospital, and Department of Psychiatry, Harvard Medical School, Charlestown, Massachusetts 02129-4404, USA.
authors.forename: Avi L
authors.initials: AL
authors.lastname: Friedlich
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Lee
authors.forename: Thomas
authors.initials: T
authors.lastname: van Groen
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cherny
authors.forename: Irene
authors.initials: I
authors.lastname: Volitakis
authors.forename: Toby B
authors.initials: TB
authors.lastname: Cole
authors.forename: Richard D
authors.initials: RD
authors.lastname: Palmiter
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Koh
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics; D027682:Cation Transport Proteins; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D003300:Copper / Q000378:metabolism; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D026901:Membrane Transport Proteins; D051379:Mice; D008822:Mice, Transgenic; D019579:Neocortex / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D013569:Synapses / Q000378:metabolism / Q000473:pathology; D015032:Zinc / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D027682:Cation Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C102806:SLC30A3 protein, human; C491177:Slc30a3 protein, mouse; D003300:Copper; D015032:Zinc