Alteration of the cerebral zinc pool in a mouse model of Alzheimer disease.
Synaptic vesicle Zn is regulated by zinc transporter 3 (ZnT3) and is involved in neurotransmission and synaptic plasticity. Here, we describe extensive alterations of ZnT3-regulated Zn 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 increased with age, there were age-dependent reductions in ZnT3 expression and synaptic Zn levels in the hippocampal mossy fiber area of Tg2576 mice. In these mice, a novel Zn 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-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 histofluorescence were also evident in activated astrocytes. These datasuggest that extensive modifications of the cerebral Zn pool, particularly synaptic Zn, may underlie neuronal dysfunction characteristic of Alzheimer disease.
Asan Institute for Life Sciences, Asan Medical Center, Seoul 138-736, Republic of Korea. jlee@amc.seoul.kr
Joo-Yong
JY
Lee
Eunsil
E
Cho
Jung-Woo
JW
Seo
Jung Jin
JJ
Hwang
Jae-Young
JY
Koh
D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D002402:Cathepsin D / Q000378:metabolism; D027682:Cation Transport Proteins; D016923:Cell Death; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000473:pathology; D050987:Vesicle-Associated Membrane Protein 1 / Q000378:metabolism; D050988:Vesicle-Associated Membrane Protein 2 / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism; D059666:Lysosomal-Associated Membrane Protein 3
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D002402:Cathepsin D; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D051907:Lysosomal Membrane Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D050987:Vesicle-Associated Membrane Protein 1; D050988:Vesicle-Associated Membrane Protein 2; D015032:Zinc; D016875:tau Proteins; C112986:AIF1 protein, human; C114233:LAMP3 protein, human; D059666:Lysosomal-Associated Membrane Protein 3; C491177:Slc30a3 protein, mouse