Deficiencies of Hippocampal Zn and ZnT3 Accelerate Brain Aging of Rat

Saito, Takeshi; Takahashi, Kyôko; Nakagawa, Noriko; Hosokawa, Toshiyuki; Kurasaki, Masaaki; Yamanoshita, Osamu; Yamamoto, Yuwako; Sasaki, Hidetada; Nagashima, Kazuo; Fujita, Hideaki

doi:10.1006/bbrc.2000.3946

Cited by 52 publications

(36 citation statements)

References 35 publications

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“…Changes in the availability of synaptic Zn 2+ might also play a role in brain aging as studies in SAMP10 mice reveal accelerated aging and reduced levels of vesicular Zn 2+ in synapses of the mossy fiber pathway (Saito et al 2000), a phenomenon most likely associated with a reduction in the expression of the Znt-3 transporter. Interestingly, these mice show increased sensitivity to excitotoxic damage in the hippocampus (Saito et al 2000), possibly due to a reduction in the tonic inhibition exerted by Zn 2+ on the activity of NMDA receptors (Vogt et al 2000).…”

Section: Zinc Oxidative Stress and Brain Agingmentioning

confidence: 99%

Oxidative stress and brain aging: is zinc the link?

et al. 2006

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Zn(2+) dyshomeostasis has been strongly linked to neuronal injury in many neurological conditions. Toxic accumulation of intracellular free Zn(2+) ([Zn(2+)](i)) may result from either flux of the cation through glutamate receptor-associated channels, voltage-sensitive calcium channels, or Zn(2+)-sensitive membrane transporters. Injurious [Zn(2+)](i) rises can also result from release of the cation from intracellular sites such as metallothioneins (MTs) and mitochondria. Chronic inflammation and oxidative stress are hallmarks of aging. Zn(2+) homeostasis is affected by oxidative stress, which is a potent trigger for detrimental Zn(2+) release from MTs. Interestingly, Zn(2+) itself is a strong inducer of oxidative stress by promoting mitochondrial and extra-mitochondrial production of reactive oxygen species. In this review, we examine how Zn(2+) dyshomeostasis and oxidative stress might act synergistically to promote aging-related neurodegeneration.

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Section: Zinc Oxidative Stress and Brain Agingmentioning

confidence: 99%

Oxidative stress and brain aging: is zinc the link?

et al. 2006

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“…The expression of ZnT3 transporter was used to visualise changes (possibly sprouting) of the mossy fibre network in the dentate gyrus (Cole et al 1999, Saito et al 2000. In control mice, there was a dense network of ZnT3-IR fibres in the polymorph layer and in the mossy fibres of the dentate gyrus (Fig.…”

Section: Unchanged Znt3 Serotonin and Nnos Immunoreactivitiesmentioning

confidence: 99%

Endocrine, liver-derived IGF-I is of importance for spatial learning and memory in old mice

Svensson¹,

Diez²,

Engel³

et al. 2006

Journal of Endocrinology

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IGF-I is a neuroprotective hormone, and neurodegenerative disorders, including Alzheimer's disease, have been associated with decreased serum IGF-I concentration. In this study, IGF-I production was inactivated in the liver of adult mice (LI-IGF-I / ), resulting in an approximately 80-85% reduction of circulating IGF-I concentrations. In young (6-month-old) mice there was no difference between the LI-IGF-I / and the control mice in spatial learning and memory as measured using the Morris water maze test. In old (aged 15 and 18 months) LI-IGF-I / mice, however, the acquisition of the spatial task was slower than in the controls. Furthermore, impaired spatial working as well as reference memory was observed in the old LI-IGF / mice. Histochemical analyses revealed an increase in dynorphin and enkephalin immunoreactivities but decreased mRNA levels in the hippocampus of old LI-IGF-I / mice. These mice also displayed astrocytosis and increased metabotropic glutamate receptor 7a-immunoreactivity. These neurochemical disturbances suggest synaptic dysfunction and early neurodegeneration in old LI-IGF-I / mice. The decline in serum IGF-I with increasing age may therefore be important for the age-related decline in memory function.

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“…ZnT3 protein levels are regulated by global genomic and non-genomic mechanisms. Estrogens (Lee et al, 2004), aging (Saito et al, 2000) and the adaptor complex AP-3 control the ZnT3 protein level (Kantheti et al, 1998;Salazar et al, 2004a). Mechanisms that regulate vesicular zinc transport independently of the ZnT3 level are largely unexplored.…”

Section: Introductionmentioning

confidence: 99%

Vglut1 and ZnT3 co-targeting mechanisms regulate vesicular zinc stores in PC12 cells

Salazar

Craige

Love

et al. 2005

Journal of Cell Science

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The lumenal ionic content of an organelle is determined by its complement of channels and transporters. These proteins reach their resident organelles by adaptordependent mechanisms. This concept is illustrated in AP-3 deficiencies, in which synaptic vesicle zinc is depleted because the synaptic-vesicle-specific zinc transporter 3 does not reach synaptic vesicles. However, whether zinc transporter 3 is the only membrane protein defining synaptic-vesicle zinc content remains unknown. To address this question, we examined whether zinc transporter 3 and the vesicular glutamate transporter Vglut1 (a transporter that coexists with zinc transporter 3 in brain nerve terminals) were co-targeted to synaptic-like microvesicle fractions in PC12 cells. Deconvolution microscopy and subcellular fractionation demonstrated that these two transporters were present on the same vesicles in PC12 cells. Vglut1 content in synaptic-like microvesicle fractions and brain synaptic vesicles was partially sensitive to pharmacological and genetic perturbation of AP-3 function. Whole-cell flow-cytometry analysis of PC12 cell lines expressing zinc transporter 3, Vglut1 or both showed that vesicular zinc uptake was increased by Vglut1 expression. Conversely, production of zinc transporter 3 increased the vesicular uptake of glutamate in a zincdependent fashion. Our results suggest that the coupling of zinc transporter 3 and Vglut1 transport mechanisms regulates neurotransmitter content in secretory vesicles.

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Deficiencies of Hippocampal Zn and ZnT3 Accelerate Brain Aging of Rat

Cited by 52 publications

References 35 publications

Oxidative stress and brain aging: is zinc the link?

Oxidative stress and brain aging: is zinc the link?

Endocrine, liver-derived IGF-I is of importance for spatial learning and memory in old mice

Vglut1 and ZnT3 co-targeting mechanisms regulate vesicular zinc stores in PC12 cells

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