Role of PGC-1α-mediated mitochondrial biogenesis in aluminum-induced learning and memory impairment in mice
Objective To explore the role of peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α)-mediated mitochondrial biogenesis in aluminum-induced learning and memory impairment in mice.Methods The adult male SPF ICR mice were randomly divided into four groups:control group(saline group),aluminum exposure groups[14,28,56 μmol/kg Al(mal)3],which were exposed for three months.The new object recognition experiment was used to detect the changes of learning and memory ability of mice.The changes of mitochondrial structure in hippocampal neurons were observed by transmission electron microscope.The content of adenosine triphosphate(ATP)in hippocampus of mice was detected by corresponding kit.The mRNA contents of PGC-1α,nuclear respiratory factor 1(NRF-1)and mitochondrial transcription factor A(TFAM)and mitochondrial DNA(mtDNA)contents were detected by reverse transcription-polymerase chain reaction(RT-PCR).The Western blotting was used to detect the expression of PGC-1α,TFAM and NRF-1 in hippocampus.Results The experimental results of new object recognition showed that the preference index and discrimination index of mice in each group decreased gradually with the increase of aluminum exposure dose(F=5.857,13.849,both P＜0.05).The results of transmission electron microscope showed that the structure of mitochondria in the control group was complete,the outer membrane and crista were clearly visible,and the mitochondria in the aluminum exposed groups showed vacuolar changes,and the normal mitochondrial structure disappeared.The contents of mtDNA and ATP in hippocampus of mice decreased gradually with the increase of aluminum exposure dose(F=313.923,89.887,both P＜0.05).Compared with the control group(1.00±0.00),the expressions of PGC-1α,NRF-1 and TFAM mRNA in hippocampal neurons in aluminum exposure groups all showed a downward trend,and the levels of PGC-1α,NRF-1 and TFAM mRNA in 56 μmol/kg Al(mal)3 group were significantly reduced to 0.53±0.08,0.21±0.08,0.42±0.06(P＜0.05).Compared with the control group(1.00±0.00),the protein expressions of PGC-1α,NRF-1 and TFAM in the aluminum exposed groups all showed a downward trend,and the protein expressions of PGC-1α,NRF-1 and TFAM in the 56 μmol/kg Al(mal)3 group decreased significantly to 0.66±0.15,0.50±0.22,0.60±0.77(P＜0.05),showing a dose-response relationship.Conclusion Aluminum can inhibit the signal pathway PGC-1α-NRF-1-TFAM related to mitochondrial biogenesis in the hippocampus of mice,decrease the number of mtDNA in neurons and inhibit intracellular mitochondrial biogenesis,reduce the ATP content in mitochondria,change the morphological structure of hippocampal neurons in mice,and then damage the learning and memory ability of mice.
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