Depression and Synaptic Zinc Regulation in Alzheimer Disease, Dementia with Lewy Bodies, and Parkinson Disease Dementia

Whitfield, David; Vallortigara, Julie; Alghamdi, Amani; Hortobágyi, Tibor; Ballard, Clive; Thomas, Alan; O’Brien, John; Aarsland, Dag; Francis, Paul T.

doi:10.1016/j.jagp.2014.05.001

Cited by 43 publications

(33 citation statements)

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“…Elevated depression scores were significantly associated with reductions in ZnT3 protein levels (Whitfield et al, 2015), an report consistent with our observations of a decrease in the level of ZnT3 protein in the PFC of subjects diagnosed with MDD and suicide victims. Since ZnT3 is responsible for loading Zn into synaptic vesicles, reduced ZnT3 may correspond to reduced level of synaptic Zn and disruption in the downstream effects of Zn (Palmiter et al, 1996; Cole et al, 1999; Linkous et al, 2008;).…”

Section: Discussionsupporting

confidence: 89%

Zinc transporters protein level in postmortem brain of depressed subjects and suicide victims

Rafało-Ulińska

Piotrowska

Kryczyk

et al. 2016

Journal of Psychiatric Research

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Background Major depressive disorder (MDD) is a serious psychiatric illness, associated with an increasing rate of suicide. The pathogenesis of depression may be associated with the disruption of zinc (Zn) homeostasis. In the brain, several proteins that regulate Zn homeostasis are present, including Zn transporters (ZnTs) which remove Zn from the cytosol. The present study was designed to investigate whether depression and suicide are associated with alterations in the expression of the ZnTs protein. Methods Protein levels of ZnT1, ZnT3, ZnT4, ZnT5 and ZnT6 were measured in postmortem brain tissue from two different cohorts. Cohort A contained 10 subjects diagnosed with MDD (7 were suicide victims) and 10 psychiatrically-normal control subjects and cohort B contained 11 non-diagnosed suicide victims and 8 sudden-death control subjects. Moreover, in cohort A we measured protein level of NMDA (GluN2A subunit), AMPA (GluA1 subunit) and 5-HT1A receptors and PSD-95. Proteins were measured in the prefrontal cortex (PFC) using Western blotting. In addition, Zn concentration was measured using a voltammetric method. Results There was a significant increase in protein levels of ZnT1, ZnT4, ZnT5 in the PFC in MDD, relative to control subjects, while ZnT3 protein level was decreased in MDD. There was no significant difference in the Zn concentration in the PFC between control and MDD subjects. Similarly, in the PFC of suicide victims (non-diagnosed), an increase in protein levels of ZnT1, ZnT4, ZnT5 and ZnT6 was observed. Conversely, protein levels of ZnT3 were decreased in both suicide victims and subjects with MDD, in comparison with control subjects. There was also a significant decrease in the protein level of GluA1, GluN2A, PSD-95 and 5-HT1A in MDD. Conclusions Our studies suggest that alterations in Zn transport proteins are associated with the pathophysiology of MDD and suicide.

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Section: Discussionsupporting

confidence: 89%

Zinc transporters protein level in postmortem brain of depressed subjects and suicide victims

Rafało-Ulińska

Piotrowska

Kryczyk

et al. 2016

Journal of Psychiatric Research

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“…On the other hand, it is relatively well established that this homeostasis is essential for correct functioning of the nervous system, because both excess and deficiency of synaptic zinc ions may cause disturbances in neuronal physiology and neurodegeneration (Weiss et al 2000; Takeda et al 2013). Probably, the involvement of ZnT3 in the regulation of synaptic Zn2 + levels is at the very heart of previously described changes in the expression of this zinc transporter during various pathological processes in the brain, including ischemia Huntington’s, Alzheimer’s and Parkinson’s diseases, epilepsy and mechanical damage (Devirgiliis et al 2007; Chi et al 2008; Whitfield et al 2015). Moreover, it is known that ZnT3 in the central nervous system may take part in regulatory processes connected both with sensory stimuli conduction and secretory activity of neuronal cells (Danscher et al 2001, 2003), and some previous studies view ZnT3 as the marker of inhibitory nerve fibers called zinc enriched nerves (ZEN) (Jo et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Co-localization of zinc transporter 3 (ZnT3) with sensory neuromediators and/or neuromodulators in the enteric nervous system of the porcine esophagus

et al. 2017

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Zinc transporter 3 (ZnT3) is one of the zinc transporters family. It is closely connected to the nervous system, where enables the transport of zinc ions from the cytoplasm to synaptic vesicles. This substance has been described within the central and peripheral nervous system, especially in the enteric nervous system (ENS). The aim of the present study was to describe the co-localization of ZnT3 with selected neuromediators and/or neuromodulators participating in sensory stimuli conduction in neurons of the ENS within the porcine esophagus. Co-localization of ZnT3 with substance P (SP), leucine enkephalin (LENK) and calcitonin gene-related peptide (CGRP) was studied using standard double-immunofluorescence technique. The obtained results show that ZnT3, SP and/or LENK may occur in the same enteric neurons, and the degree of co-localization of these substances clearly depends on the fragment of esophagus studied and the type of enteric ganglia. In contrast, the co-localization of ZnT3 with CGRP was not observed during the present investigation. The obtained results suggest that ZnT3 in the ENS may be involved in the conduction of sensory and/or pain stimuli.

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“…A rendelkezésre álló adatok és a klinikai tapasztalat alapján a szerotonerg szerek kevéssé tolerálhatók, valamint depressziós és szorongásos tünetekre való hatásukban sem jelentősek ebben a betegcsoportban [72]. Egy kö-zelmúltban megjelent tanulmány szignifikáns összefüg-gést mutatott ki a cinkmetabolizmus csökkenése és a depresszió kialakulása között, így ennek befolyásolása ígéretes terápiás célpont lehet a jövőben [74].…”

Section: Terápiás Megfontolásokunclassified

A Lewy-testes demencia klinikai és neuropatológiai jellemzői

et al. 2017

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A Lewy-testes demencia a második leggyakoribb neurodegeneratív demencia. A pontos diagnózisa gyakran csak neuropatológiai vizsgálattal lehetséges. A betegség fő morfológiai jellemzője a kóros α-szinukleinben gazdag Lewy-test és Lewy-neurit -csakúgy, mint a rokon kórkép Parkinson-kór és az ahhoz társuló demencia esetén. A patomechanizmus fontos tényezői a neurotranszmitter rendszerek zavara, a szinaptikus diszfunkció és az ubikvitin-proteaszóma rendszer elégtelen működése. Jellemző a kognitív teljesítmény fluktuációja, parkinsonizmus és vizuális hallucináció. Mivel gyakran nem típusos a klinikai kép és időbeni lefolyás, a képalkotó eljárások és biomarkerek elősegíthetik a korai felismerést. Noha hatékony oki terápia nincs, életminőséget javító kezelések lehetségesek. A klinikopatológiai vizsgálatok kiemelten fontosak a patomechanizmus jobb megértése, a pontos diagnózis és a hatékony terápia érdeké-ben. Orv Hetil. 2017; 158(17): 643-652.Kulcsszavak: Lewy-testes demencia, neuropatológia, biomarkerek, Parkinson-kór, α-szinuklein Clinical and neuropathological characteristics of dementia with Lewy bodiesDementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia. The accurate diagnosis is often possible only by neuropathological examination. The morphologic hallmarks are the presence of α-synuclein-rich Lewy bodies and Lewy neurites, identical to those seen in Parkinson's disease (PD) and Parkinson's disease dementia (PDD). Neurotransmitter deficits, synaptic and ubiquitin-proteasome system (UPS) dysfunction play major role in the pathomechanism. Characteristic symptoms are cognitive fluctuation, parkinsonism and visual hallucinations. Due to the often atypical clinical presentation novel imaging techniques and biomarkers could help the early diagnosis. Although curative treatment is not available, therapies can improve quality of life. Clinicopathological studies are important in exploring pathomechanisms, ensuring accurate diagnosis and identifying therapeutic targets.

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Depression and Synaptic Zinc Regulation in Alzheimer Disease, Dementia with Lewy Bodies, and Parkinson Disease Dementia

Cited by 43 publications

References 37 publications

Zinc transporters protein level in postmortem brain of depressed subjects and suicide victims

Zinc transporters protein level in postmortem brain of depressed subjects and suicide victims

Co-localization of zinc transporter 3 (ZnT3) with sensory neuromediators and/or neuromodulators in the enteric nervous system of the porcine esophagus

A Lewy-testes demencia klinikai és neuropatológiai jellemzői

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