Changes in transcription of genes encoding NAD-dependent enzymes and mitochondrial proteins in Alzheimer’s disease animal model. Indication of early targets in neuroprotection

Abstract

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.