ZnT3 mRNA levels are reduced in Alzheimer's disease post-mortem brain
1 Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Northern Ireland
2 Genomics Core Facility, Queen's University Belfast, Regional Genetics Centre, Belfast City Hospital, Northern Ireland
3 Brain Bank Consultants, Netherlands Institute for Neurosciences, Meibergdreef 47, 1105 BA Amsterdam, the Netherlands
4 Center for Medical Genetics Ghent, Ghent University Hospital, B-9000 Ghent, Belgium
Molecular Neurodegeneration 2009, 4:53 doi:10.1186/1750-1326-4-53Published: 23 December 2009
ZnT3 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.
We 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.
This 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.