Zinc Transporter mRNA Levels in Alzheimer's Disease Postmortem Brain

Abstract

Zinc (Zn2+) is concentrated into pre-synaptic vesicles and co-released with neurotransmitter at some synapses. Zn2+ can accelerate assembly of the amyloid-β peptides (Aβ) and tau protein central to the neuropathological changes found in Alzheimer's disease (AD). Altered protein levels of the membrane Zn2+ transporters ZnT1, ZnT4, and ZnT6 have been reported in AD postmortem brain tissue. The present study analyzed mRNA levels of five established (LIV1, ZIP1, ZnT1, ZnT4, and ZnT6) and one potential (PRNP) Zn2+ transporter in human postmortem brain tissue from Braak-staged individuals with AD and controls using quantitative real-time PCR. Four cortical regions (middle temporal gyrus, superior occipital gyrus, superior parietal gyrus, and superior frontal gyrus) and cerebellum were examined. PRNP mRNA levels were decreased by ∼30% in all four cortical regions examined in AD patients, but unchanged in the cerebellum. In contrast, some increases in mRNA levels of the other more established Zn2+ transporters (LIV1, ZIP1, ZnT1, ZnT6) were found in AD cortex. The ratios of the mRNA levels of LIV1, ZIP1, ZnT1, ZnT4, and ZnT6/mRNA level of neuron specific enolase increased significantly as the disease progressed and Braak stage increased. Significant correlations were also identified between mRNA levels of several of the Zn2+ transporters investigated. These expression changes could either reflect or cause the altered cortical Zn2+ distribution in AD, potentially increasing the likelihood of interactions between Zn2+ and Aβ or tau protein.

Zinc homeostasis and neurodegenerative disorders

“…Recent studies showed alterations in levels of ZnTs proteins in the brain of subjects diagnosed with the preclinical stage of AD (PCAD), mild cognitive impairment (MCI), early (EAD), and the late (LAD) stage of AD when compared to the control subjects (Lovell et al, 2005, 2006; Smith et al, 2006; Lovell, 2009; Lyubartseva et al, 2010; Lyubartseva and Lovell, 2012). Human postmortem brain tissue from Braak-staged individuals with AD displayed a reduced expression of ZnT-3 mRNA (Beyer et al, 2009) and increased mRNA levels of the other more established zinc transporters, such as LIV1, ZIP1, ZnT1, ZnT6 in the AD cortex (Beyer et al, 2012). Also animal studies have linked dyshomeostasis in the brain zinc level to the pathogenesis and progression of AD.…”

Zinc and the aging brain

“…As zinc bound to Ab oligomers can disrupt synaptic function and contribute to neuronal cell death, decreased ZnT3 expression may result from the selective loss of zinc-secreting synapses. While Znt1 expression is increased in the temporal lobe of patients with early-or late-onset AD, low levels are associated with PCAD and mild cognitive impairment (MCI) (Lovell et al 2005;Lyubartseva et al 2010;Beyer et al 2012). A recent study found that mRNA levels of several zinc transporters (ZIP 1 and 6 as well as ZnT 1, 4, and 6) increase with AD progression correlating with NFT accumulation (Beyer et al 2012).…”

“…While Znt1 expression is increased in the temporal lobe of patients with early-or late-onset AD, low levels are associated with PCAD and mild cognitive impairment (MCI) (Lovell et al 2005;Lyubartseva et al 2010;Beyer et al 2012). A recent study found that mRNA levels of several zinc transporters (ZIP 1 and 6 as well as ZnT 1, 4, and 6) increase with AD progression correlating with NFT accumulation (Beyer et al 2012). Therefore, further analysis of zinc distribution in PCAD and MCI is required to further our understanding of how zinc metabolism changes through AD progression.…”

X-ray fluorescence imaging reveals subcellular biometal disturbances in a childhood neurodegenerative disorder

“…This potentially reflects the size and complexity of the zinc proteome, predicted to encompass approximately 2800 catalytic and regulatory proteins with an array of varied cellular functions 61 . Altered expression of Zip and ZnT proteins has been reported for various neurodegenerative disorders, including AD 62, 63 and Friedrich’s Ataxia 64 . We have also detected loss of Zip7 in 3 natural CLN6 disease models (Fig.…”