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The Journal of Neuroscience, March 31, 2004, 24(13):3453-3459; doi:10.1523/JNEUROSCI.0297-04.2004

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Neurobiology of Disease
Neuronal Zinc Exchange with the Blood Vessel Wall Promotes Cerebral Amyloid Angiopathy in an Animal Model of Alzheimer's Disease

Avi L. Friedlich,^1 * Joo-Yong Lee,^2 * Thomas van Groen,³ Robert A. Cherny,^4,5 Irene Volitakis,^4,5 Toby B. Cole,⁶ Richard D. Palmiter,⁶ Jae-Young Koh,² and Ashley I. Bush^1,4,5

¹Laboratory for Oxidation Biology, Genetics and Aging Research Unit, Massachusetts General Hospital, and Department of Psychiatry, Harvard Medical School, Charlestown, Massachusetts 02129-4404, ²National Creative Research Initiative Center for the Study of CNS Zinc, University of Ulsan College of Medicine, Seoul 138-736, Korea, ³Department of Neuroscience and Neurology, University of Kuopio, Kuopio FIN 70211, Finland, ⁴Mental Health Research Institute of Victoria, Parkville, Victoria 3052, Australia, ⁵Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia, and ⁶Howard Hughes Medical Institute, Department of Biochemistry, University of Washington, Seattle, Washington 98195

Cerebral amyloid angiopathy (CAA) is common in Alzheimer's disease (AD) and may contribute to dementia and cerebral hemorrhage. Parenchymal -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 -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.

Key words: Alzheimer; blood–brain; neuropathology; synapse; zinc; amyloid; cerebrovasculature; congophilic angiopathy

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Received Dec 8, 2003; revised February 20, 2004; accepted February 21, 2004.

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