Neuronal zinc exchange with the blood vessel wall promotes cerebral amyloid angiopathy in an animal model of Alzheimer's disease.
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.
Friedlich
Avi L
AL
Laboratory for Oxidation Biology, Genetics and Aging Research Unit, Massachusetts General Hospital, and Department of Psychiatry, Harvard Medical School, Charlestown, Massachusetts 02129-4404, USA.
Lee
Joo-Yong
JY
van Groen
Thomas
T
Cherny
Robert A
RA
Volitakis
Irene
I
Cole
Toby B
TB
Palmiter
Richard D
RD
Koh
Jae-Young
JY
Bush
Ashley I
AI
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*
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