Obesity and age-related alterations in the gene expression of zinc-transporter proteins in the human brain.
The incidence of Alzheimer's disease (AD) is increasing. Major risk factors for AD are advancing age and diabetes. Lately, obesity has been associated with an increased risk of dementia. Obese and diabetic individuals are prone to decreased circulating levels of zinc, reducing the amount of zinc available for crucial intracellular processes. In the brain, zinc co-localizes with glutamate in synaptic vesicles, and modulates NMDA receptor activity. Intracellular zinc is involved in apoptosis and fluctuations in cytoplasmic Zn(2+) affect modulation of intracellular signaling. The ZNT and ZIP proteins participate in intracellular zinc homeostasis. Altered expression of zinc-regulatory proteins has been described in AD patients. Using microarray data from human frontal cortex (BrainCloud), this study investigates expression of the SCLA30A (ZNT) and SCLA39A (ZIP) families of genes in a Caucasian and African-American sample of 145 neurologically and psychiatrically normal individuals. Expression of ZNT3 and ZNT4 were significantly reduced with increasing age, whereas expression of ZIP1, ZIP9 and ZIP13 were significantly increased. Increasing body mass index (BMI) correlated with a significant reduction in ZNT1 expression similar to what is seen in the early stages of AD. Increasing BMI also correlated with reduced expression of ZNT6. In conclusion, we found that the expression of genes that regulate intracellular zinc homeostasis in the human frontal cortex is altered with increasing age and affected by increasing BMI. With the increasing rates of obesity throughout the world, these findings warrant continuous scrutiny of the long-term consequences of obesity on brain function and the development of neurodegenerative diseases.
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
R H
RH
Olesen
Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
T M
TM
Hyde
Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
J E
JE
Kleinman
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
K
K
Smidt
Department of Biomedicine, Aarhus University, Aarhus, Denmark.|Center for Diabetes Research, Gentofte University Hospital, Hellerup, Denmark.
J
J
Rungby
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
A
A
Larsen
D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000503:physiopathology; D015992:Body Mass Index; D002352:Carrier Proteins / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D030541:Databases, Genetic; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism*; D015870:Gene Expression / Q000235:genetics*; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D008875:Middle Aged; D009765:Obesity / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics; D012307:Risk Factors; D013223:Statistics as Topic; D014157:Transcription Factors / Q000235:genetics*; D044465:White People / Q000235:genetics*; D015032:Zinc / Q000378:metabolism; D000097809:Transcription Factor MTF-1
D002352:Carrier Proteins; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D015032:Zinc; D000097809:Transcription Factor MTF-1; C102806:SLC30A3 protein, human; C491597:SLC30A4 protein, human; C403517:SLC39A1 protein, human; C521172:SLC39A13 protein, human; C543108:Slc39a9 protein, human; C017800:zinc-binding protein