Seizures and neuronal damage in mice lacking vesicular zinc

Cole, Toby B.; Robbins, Carol A.; Wenzel, H. Jürgen; Schwartzkroin, Philip A.; Palmiter, Richard D.

doi:10.1016/s0920-1211(99)00121-7

Cited by 210 publications

(159 citation statements)

References 71 publications

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“…hAPP ϩ mice lacking ZnT3 exhibited no differences from wild-type mice with respect to body size, gross morphology, fertility, longevity, or behavior. Moreover, brain regions that normally have abundant synaptic zinc appear normal by light and electron microscopies (26), although there is an increased susceptibility of these mice to kainate-induced seizures (28).…”

Section: Resultsmentioning

confidence: 99%

Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice

Lee

Cole

Palmiter

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

393

280

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Endogenous metals may contribute to the accumulation of amyloid plaques in Alzheimer's disease. To specifically examine the role of synaptic zinc in the plaque accumulation, Tg2576 (also called APP2576) transgenic mice (hAPP ؉ ) expressing cerebral amyloid plaque pathology were crossed with mice lacking zinc transporter 3 (ZnT3 ؊/؊ ), which is required for zinc transport into synaptic vesicles. With aging, female hAPP ؉ :ZnT3 ؉/؉ mice manifested higher levels of synaptic zinc, insoluble amyloid ␤, and plaques than males; these sex differences disappeared in hAPP ؉ :ZnT3 ؊/؊ mice. Both sexes of hAPP ؉ :ZnT3 ؊/؊ mice had markedly reduced plaque load and less insoluble amyloid ␤ compared with hAPP ؉ :ZnT3 ؉/؉ mice. Hence, of endogenous metals, synaptic zinc contributes predominantly to amyloid deposition in hAPP ؉ mice.

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Section: Resultsmentioning

confidence: 99%

Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice

Lee

Cole

Palmiter

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

393

280

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“…Upon stimulation, vesicular zinc ions are released (Assaf and Chung 1984;Charton et al 1985;Aniksztejn et al 1987) and may enter the postsynaptic neurons via ionotropic glutamate receptors and calcium channels (Sensi et al 1997;Choi and Koh 1998;Weiss and Sensi 2000). This translocation of chelatable zinc ions from presynaptic terminals to postsynaptic neurons has been proposed to play an important role in the selective neuronal death resulting from ischemia, status epilepticus and trauma Tonder et al 1990;Koh et al 1996;Suh et al 2000; except for Cole et al 2000). Consistent with our in vitro observation that zinc ions promote the assembly of the PSD, after transient cerebral ischemia, a condition that lead to the accumulation of chelatable zinc in neurons (Tonder et al 1990;Koh et al 1996), the PSDs of hippocampal neurons became significantly thicker (Hu et al 1998).…”

Section: Discussionmentioning

confidence: 99%

Structural role of zinc ions bound to postsynaptic densities

Jan

Chen

Tsai

et al. 2002

Journal of Neurochemistry

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Postsynaptic densities (PSDs) isolated from porcine cerebral cortices are large aggregates consisting of more than 30 different proteins. Inductively coupled plasma-mass spectrometric analyses revealed that isolated PSDs contained zinc at a concentration of 4.1 nmol per mg protein. Treatment with 8 M urea lead to dissociation of the PSDs into small components and, concomitantly, depletion of most of their bound zinc. After removal of the urea by dialysis, urea-dissociated PSD proteins did not reassemble into aggregates by themselves. Adding ZnCl 2 to urea-treated PSD samples resulted in the assembly of urea-dissociated proteins into large aggregates with morphology and protein composition closely resembling those of the original PSDs. Mg 2+ , Ca 2+ , Co 2+ , Cd 2+ , Cu 2+ , Mn 2+ , Fe 3+ , K + and Na + ions at higher concentrations also induced the aggregation of urea-dissociated PSD protein. The structures of the K + -, Na + -, Mg 2+ -and Ca 2+ -induced aggregates were distinct from that of the original PSDs. Our results indicate that the structure of the PSD could be disassembled and reassembled under in vitro conditions. They further suggest that Zn 2+ ions, by binding to certain zincbinding proteins, play an important role in the formation and maintenance of the structure of the PSD.

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“…Late-onset iron deposition was also observed after transient focal ischemia in rat brain (Kondo et al, 1995). The transition metal Zn 2+ mediates the death of neuronal and non-neuronal cells in hypoxic-ischemia, epilepsy, and trauma (Koh et al, 1996;Cole et al, 2000;Lee et al, 2000;Suh et al, 2000). Zn 2+ is stored in the presynaptic vesicles of glutamatergic neurons, released with glutamate in an activity dependent manner, and translocated into adjacent neurons (Frederickson and Moncrieff, 1994).…”

Section: Production Of Reactive Oxygen Species By Transition Metalsmentioning

confidence: 98%

Cellular and Molecular Pathways of Ischemic Neuronal Death

Won¹,

Kim²,

Gwag³

2002

BMB Reports

201

172

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Three routes have been identified triggering neuronal death under physiological and pathological conditions. Excess activation of ionotropic glutamate receptors cause influx and accumulation of Ca 2+ and Na + that result in rapid swelling and subsequent neuronal death within a few hours. The second route is caused by oxidative stress due to accumulation of reactive oxygen and nitrogen species. Apoptosis or programmed cell death that often occurs during developmental process has been coined as additional route to pathological neuronal death in the mature nervous system. Evidence is being accumulated that excitotoxicity, oxidative stress, and apoptosis propagate through distinctive and mutually exclusive signal transduction pathway and contribute to neuronal loss following hypoxic-ischemic brain injury. Thus, the therapeutic intervention of hypoxic-ischemic neuronal injury should be aimed to prevent excitotoxicity, oxidative stress, and apoptosis in a concerted way.

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Seizures and neuronal damage in mice lacking vesicular zinc

Cited by 210 publications

References 71 publications

Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice

Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice

Structural role of zinc ions bound to postsynaptic densities

Cellular and Molecular Pathways of Ischemic Neuronal Death

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