Peroxisome proliferator-activated receptors α (PPARα) are members of the nuclear receptors family and a very potent transcription factor engaged in the regulation of lipid and energy metabolism. Recent data suggest that PPARα could play an important role in the pathomechanism of Alzheimer's disease (AD) and other neuropsychiatric disorders. This study focused on the effect of a synthetic ligand of PPARα, GW7647 on the transcription of genes encoding proteins of mitochondria biogenesis and dynamics in the brain of AD mice. The experiments were carried out using 12-month-old female FVB-Tg mice with the V717I mutation of amyloid precursor protein (APP + ) and mice without the transgene (APP -). Moreover, APP + and APPmice were treated for 14 days with GW7647 administered subcutaneously with a dose 5 mg/kg b.w. Brain cortex was used and qRT-PCR was performed. Our data indicated that GW7647 upregulated the expression of genes encoding proteins of mitochondria biogenesis in ADTg mice. GW7647 enhanced the level of mRNA of Ppargc1, Nrf2 and Tfam in APP + as compared to APP -mice treated with GW7647. Moreover, our studies demonstrated that GW7647 had no effect on genes that regulate mitochondria fission and fusion of ADTg mice as correlated to mice without the transgene. Our results indicate that the ligand of PPARα, GW7647 may exert a promising neuroprotective effect through the regulation of transcription of genes coding proteins of mitochondria biogenesis. These data suggest that activation of PPARα at an early stage of AD could be a helpful strategy for slowing the progression of neurodegeneration.

Oxidative stress and disturbances of mitochondria function in the brain play a crucial role in Alzheimer’s disease (AD). However, little is known about these changes at the early stages of AD. This study aimed to determine the expression of genes encoding superoxide dismutase’s (SOD1, SOD2), Sirtuins (SIRTs) and poly (ADP-ribose) polymerases (PARPs). Moreover, transcription of genes of electron transport complexes (ETC) and proteins of mitochondrial biogenesis in the brain cortex of 3-, 6- and 12-month-old transgenic AD mice was analyzed. Using quantitative qPCR and immunochemical methods, we demonstrated significant decreases in mRNA of Sod2, Sirt1 and Parp1 in the 3-month-old and upregulation of Parp1 in the 6-month-old AD mice. Although levels of mRNA encoding ETC, respiratory complexes subunits (I-II) were negligibly altered, the mRNA mt-CytB and mt-Co1 (complex III, IV) was increased in 12- and 6-month-old AD brains, respectively. These changes were linked to lower cytochrome C oxidase activity in 3- and significantly in 6-month-old AD mice. Several genes involved in mitochondria biogenesis, such as Nrf1, Nrf2 and Tfam, were upregulated in the 3- and 6-month-old AD Tg brain. However, in 12-month-old AD mice, transcription of genes encoding NRF2, PPAR-α, and PGC1-α was significantly downregulated. In summary, our data identified significant changes in gene expression of Sod2, Sirt1 and Parp1 at an early age (3–6 month-old AD mice) and Nrf2, Ppargc1, Ppar-α at the later stage of AD mice. Recognizing these alterations earlier may be important in providing potential therapeutic targets for delaying the progression of pathology in AD.

Oxidative stress and disturbances of mitochondria function in the brain have been recognized to play a crucial role in the pathophysiological mechanism of Alzheimer’s Disease (AD). However, little is known about these changes at an early age of AD, which could be crucial for therapeutic strategy for the disease. In this study, we used biochemical, and quantitative polymerase chain reaction for determination of expression of genes encoding enzymes related to the antioxidative defence including Sirtuins (Sirts) and DNA-bound poly (ADP-ribose) polymerases (PARPs). Moreover, expression of genes related to mitochondrial dynamic, biogenesis and function in the brain cortex of 3- and 6-month-old FVB mice with London mutation (V7171) was analysed and compared with mice without transgene. Results indicated significant decreases in mRNA expression encoding SOD2, Sirt1 and PARP1 in the 3-month-old AD Tg mice and an increase in expression of PARP-1 in the 6-month-old AD Tg. Although levels of mRNA encoding subunits of mitochondrial respiratory complexes (I-III) were negligible altered, there was upregulation of gene encoding subunit of complex IV and proteins related to mitochondria biogenesis and dynamic, such as the Neuronal Respiratory Factors (NRF1) and NRF2, Opa1, Fis1, and Drp1 in the AD mice. Our data indicate downregulation of genes related to antioxidation and activation of genes encoding mitochondrial biogenesis and fission / fusion at early age of the AD mice. The ability to identify changes in gene expression for Sirt1, SOD2, Fis1 and Drp1 at an early age suggest potential therapeutic targets for retarding the pathological progression in AD.