Alteration of the cerebral zinc pool in a mouse model of Alzheimer disease

Abstract

Synaptic vesicle Zn 2+ is regulated by zinc transporter 3 (ZnT3) and is involved in neurotransmission and synaptic plasticity. Here, we describe extensive alterations of ZnT3-regulated Zn 2+ pools in the brains of human amyloid precursor protein-transgenic (Tg2576) mice. In contrast to wild-type littermates in which ZnT3 expression and synaptic Zn 2+ increased with age, there were age-dependent reductions in ZnT3 expression and synaptic Zn 2+ levels in the hippocampal mossy fiber area of Tg2576 mice. In these mice, a novel Zn 2+ pool and ZnT3 expression were colocalized and appeared along dystrophic neurites surrounding compact amyloid plaques that were identified by in situ blue fluorescence, congophilic birefringence, and Aβ42 immunoreactivity. Zn 2+-specific histofluorescence and ZnT3 immunofluorescence in dystrophic neurites were also colocalized with the δ-subunit of adaptor protein complex 3, lysosome-associated membrane protein, cathepsin D, and neurofilament-containing hyperphosphorylated paired helical filaments. The synaptic vesicle marker protein synaptophysin and vesicle-associated membrane protein were not found in these neurites, suggesting a role of ZnT3 distinct from itsnormal role in synaptic Zn. ZnT3 immunoreactivity and Zn 2+ histofluorescence were also evident in activated astrocytes. These datasuggest that extensive modifications of the cerebral Zn 2+ pool, particularly synaptic Zn, may underlie neuronal dysfunction characteristic of Alzheimer disease. Copyright © 2012 by the American Association of Neuropathologists, Inc.