Effects Of Melatonin On Mitochondrial Biogenesis In Animal Models Of Alzheimer's Disease

BackgroundAlzheimer's disease(AD)is a common neurological disease.The elderly have frequent onset,latent seizures and slow and irreversible progress.AD has a very complex etiology and pathogenesis,and the specific mechanism is not yet clear.In the treatment of AD,there is lack of effective treatment,mainly symptomatic treatment.Therefore,it is an important medical problem to study the etiology and pathogenesis of AD and find out effective prevention and cure measures.XMitochondrial biogenesis damage was observed in AD patients and models for a long time.More and more experimental evidence suggests that mitochondrial biogenesis is involved in the pathogenesis of AD,but the exact mechanism is still unclear.In this study,the expression of amyloid-(3 precursor protein(APP)and presenilin 1(PS1)in APPswe/PS1dE9 transgenic mice was successf'ully constructed.The AD mouse model was established.We then compared the experimental APPswe/PS1dE9 transgenic mice with melatonin(0.5 mg/d)in drinking water for 4 to 8 months.No melatonin was added to APPswe/PS1dE9 transgenic mice and C57BL/6J mice in control group.The expression levels of mitochondrial transcription factor A,nuclear respiratory factor 1,nuclear respiration factor 2,peroxisome proliferator-activated receptor y coactivator la,and mitochondrial ultrastructure were observed.Mitochondrial DNA and Nuclear DNA ratio,spatial learning and memory of mice,A? deposition and soluble A ? level in cerebral cortex and hippocampus.Compared with the control group,the levels of mitochondrial biogenesis regulators,mitochondrial ultrastructure damage,mtDNA copy number and spatial learning and memory impairment in APPswe/PS1dE9 transgenic mice fed with melatonin for a long time were increased.The deposition of A? and soluble A? decreased in cerebral cortex and hippocampus of mice.Therefore,we hypothesized that the dysfunction of AD midline somal biogenesis might damage the structure and function of mitochondria.Melatonin can reduce AD through promoting mitochondrial biogenesis.Methods1.APP/PS1 double transgenic mice with C57BL/6J mice as genetic background were used as animal models of AD.C57BL/6J mice and APP/PS1 mice drinking PBS as control group and APP/PS1 mice drinking PBS dissolved melatonin as experimental group were fed under the same feeding conditions for 4 months.2.The expression levels of mitochondrial biogenesis proteins,PGC-la and NRF1,NRF2,TFAM were detected by Western blotting.3.Ultrastructure of mitochondria in mouse cortical and hippocampal neurons by transmission electron microscope.4.Detection of mtDNA expression:in cortex and hippocampus of mice by Real-Time PCR.5.Observation of learning and memory ability of mice by water maze.6.Observation of senile plaques in cortex and hippocampus of mice by thiocyanin staining.7.Expression of A?1-40 and A?1-42 in cortex and hippocampus of mice detected by Elisa.Results1.Compared with C57 mice,the expression of PGC-1?,.NRF1,NRF2 and TFAM in cerebral cortex and hippocampus of APP/PS1 mice was lower than that in C57 mice,and that in mitochondria biogenesis was decreased after 4 months of melatonin treatment.2.Compared with C57 mice,the mitochondria of CA1 neurons in cerebral cortex and hippocampus of APP/PS1 mice were swollen and cristal rupture,and the damage of mitochondria structure was alleviated after 4 months of melatonin treatment.3.Compared with C57 mice,the content of mitochondrial DNA(mtDNA)in cerebral cortex and hippocampus of APP/PS1 mice was decreased,and the content of mtDNA increased after 4 months of melatonin treatment.4.Compared with C57 mice,the spatial learning and memory ability of APP/PS1 mice was decreased.and the spatial learning and memory ability of AD mice was improved after 4 months of melatonin treatment.5.Compared with C57 mice,a large number of senile plaques appeared in the cerebral cortex and hippocampus of APP/PS1 mice,and the expression levels of A?40 and A?42 decreased significantly in cerebral cortex and hippocampus of AD mice after 4 months of melatonin treatment.ConclusionThis study showed that the reduce of mitochondrial biogenesis signaling in the AD mouse model.Defective mitochondrial biogenesis may contribute to mitochondrial dysfunction in AD.and melatonin,which can enhance mitochondrial biogenesis,may be a potential approach for the treatment of AD.