ZnT3 mRNA levels are reduced in Alzheimer's disease post-mortem brain

Abstract

BackgroundZnT3 is a membrane Zn2+ transporter that is responsible for concentrating Zn2+ into neuronal presynaptic vesicles. Zn2+ homeostasis in the brain is relevant to Alzheimer's disease (AD) because Zn2+ released during neurotransmission may bind to Aβ peptides, accelerating the assembly of Aβ into oligomers which have been shown to impair synaptic function.ResultsWe quantified ZnT3 mRNA levels in Braak-staged human post mortem (pm) brain tissue from medial temporal gyrus, superior occipital gyrus, superior parietal gyrus, superior frontal gyrus and cerebellum from individuals with AD (n = 28), and matched controls (n = 5) using quantitative real-time PCR. ZnT3 mRNA levels were significantly decreased in all four cortical regions examined in the AD patients, to 45-60% of control levels. This reduction was already apparent at Braak stage 4 in most cortical regions examined. Quantification of neuronal and glial-specific markers in the same samples (neuron-specific enolase, NSE; and glial fibrillary acidic protein, GFAP) indicated that loss of cortical ZnT3 expression was more pronounced, and occurred prior to, significant loss of NSE expression in the tissue. Significant increases in cortical GFAP expression were apparent as the disease progressed. No gene expression changes were observed in the cerebellum, which is relatively spared of AD neuropathology.ConclusionsThis first study to quantify ZnT3 mRNA levels in human pm brain tissue from individuals with AD and controls has revealed a significant loss of ZnT3 expression in cortical regions, suggesting that neuronal cells in particular show reduced expression of ZnT3 mRNA in the disease. This suggests that altered neuronal Zn2+ handling may be an early event in AD pathogenesis.

Cognitive Loss in Zinc Transporter-3 Knock-Out Mice: A Phenocopy for the Synaptic and Memory Deficits of Alzheimer's Disease?

“…Our results of decreased ZnT3 in AD are consistent with a decrease in ZnT3 mRNA recently reported (Beyer et al, 2009).…”

Heterodimerization, Altered Subcellular Localization, and Function of Multiple Zinc Transporters in Viable Cells Using Bimolecular Fluorescence Complementation

“…For example, ZnT2 is up-regulated in the mammary gland during lactation through the elevation of prolactin, which acts as a transcriptional transactivator (41). As an example of a pertaining pathological state, ZnT3 mRNA levels were shown to be markedly reduced in brain tissue from patients with Alzheimer disease (42). Although women carrying the G87R-ZnT2 mutation did not show other known related symptoms except for low levels of zinc in their breast milk (11,13), based on our current data instigating heterodimerization of ZnT2 with ZnT1, ZnT2 with ZnT3, and ZnT2 with ZnT4, it is possible that the dominant negative effect of the G87R-ZnT2 mutant mediates additional pathologic alterations on other ZnTs that were not described before.…”

ZnT3: a zinc transporter active in several organs

“…These findings may support the theory that ZnT3 is involved in the formation of senile plaques and cerebral amyloid angiopathy. On the contrary, another study demonstrated that in human post mortem brain tissue Znt3 transcription is 45-60% down-regulated in cortical regions of people with diagnosed Alzheimer's disease (Beyer et al 2009). This result is supported by the findings from Adlard et al who found a decline in the ZnT3 level of people suffering from Alzheimer's disease compared to controls (Adlard et al 2010).…”