It is widely suggested that activation of free radicals, oxidative stress and alterations of mitochondrial functions are crucial pathophysiological mechanisms of neurodegenerative disorders including Alzheimer’s disease (AD) (Wang et al., 2020; Schmitt et al., 2012; Oliver and Reddy, 2019). Mitochondria are responsible not only for ATP biosynthesis but also for nicotine adenine dinucleotide (NAD) synthesis, and NAD is the substrate for an important family of enzymes such as Sirtuins (histone deacetylase type III, ) and poly(ADP-ribose)polymerases (PARPs). Mitochondria dysfunctions could lead to activation of free radical cascade which may evoke changes in several transcription factors including peroxisomes proliferator activated receptors (PPARs) and alterations of genes expression involved in amyloid beta precursor protein (APP) metabolism and release of amyloid beta (Aβ) peptides. Environmental factors and systemic inflammation could lead to alteration of redox homeostasis, free radical liberation, and molecular changes evoked also by modulation of NAD-dependent enzymes such as histone deacetylases type III, Sirtuins and DNA bound poly (ADP-ribose) polymerases (PARP1, PARP2, PARP3) (Cantó et al., 2013). These changes may induce mitochondria failure and suppress activity of electron transport chain (ETC). Consequently, free radicals may activate cascades of events leading to oxidative stress, synaptic dysfunctions, cells degeneration and death (Schmitt et al 2012; Czapski et al., 2017).
Mitochondrial dysfunction has been shown to occur early in neurodegenerative disorders, including the initial stage of AD (Reddy et al., 2012). In AD brain, oxidative damage leading to alteration of mitochondria membrane permeability can lead to alterations of Ca2+ channels and stimulate Ca2+ dependent processes which may further activate the free radical cascade and resulting in generation of pro-apoptotic signals and mitochondria fission (Moneim, 2015; Manczak et al., 2016; Yang et al., 2021). Fission and fusion of mitochondria are highly modulate by free radical production, oxidative stress, and alteration of ion homeostasis within the cell.
Despite of an abundance of literature about mitochondria failure in neurodegeneration, our understanding of the processes underlying their dysfunction in different part of the brain in AD and other neurodegenerative disorders is still limited. Substantial studies have revealed that alterations of mitochondria in neuronal cells and in synaptic endings are early pathophysiological events in AD (Schmitt et al., 2012; Du et al., 2012). Nevertheless, questions on this subject including sequence of molecular events and their localization in particular brain regions have not yet been fully resolved. Moreover, the role of protective processes activated simultaneously with pathological changes is not well recognized. There is indication that energy production not only is related to complexes/super complexes of the electron transport chain (ETC) but also is dependent on mitochondrial dynamic and their ability to undergo cycles of fission and fusion (Manczak et al., 2016; Oliver and Reddy, 2019). Mitochondrial dynamic machinery depends mainly on dynamin related protein 1 (Drp1), mitochondria fission protein 1 (Fis1), mitochondria fission factor (Mff), and proteins regulating mitochondrial fusion, e.g., mitofusin-1, mitofusin-2 (Mfn1, Mnf2) and optical atrophy protein 1 (Opa1). These proteins are known to participate in the assembly and stability of ETC super complexes, in remodeling of mitochondrial cristae, and in shaping mitochondrial morphology in response to environmental conditions. However, only 13 proteins involved in mitochondria function are encoding by mtDNA. The nuclear respiratory factors, NRF1 and NRF2, are implicated in the transcription of genes encoding respiratory subunits, including 10 subunits of cytochrome c oxidase of complex IV, and transcription factor A mitochondria (TFAM) and both TFB (Transcription factor B) isoforms. Moreover, members of the nuclear receptors (NRs) superfamily including PPAR-α can also play a significant role in the transcriptional control and in mitochondrial lipids and fatty acids metabolism (Wójtowicz et al., 2020, Strosznajder et al., 2021).
Recent studies demonstrated excessive mitochondria division in AD patients and in experimental animal models of AD (Hu et al., 2017; Wang et al., 2020; Oliver and Reddy, 2019). Our data from Cieślik et al. (2020) showed significant downregulation of genes such as Sirt 1, mt-Nd1, Mfn1 and concomitant upregulation of Dnm1 in the 12-month-old AD Tg mice model (with London mutation). In the human AD brain, changes in microRNA patterns (miRNA-9, miRNA-34a, miRNA-146 and miRNA-155) were found, and these changes are probably responsible for the downregulation of Sirt1 expression (Cieslik et al., 2020). Alterations of transcription of genes encoding proteins related to mitochondria biogenesis can also affect the progression of AD. Through interaction with NRF1, PGC-1α (Peroxisome Proliferator-Activated Receptor Gamma Coactivator alpha), the key protein of mitochondria biogenesis, can lead to activation of gene coding TFAM and then mitochondrial DNA (mtDNA). This transcription factor TFAM is crucial not only for mtDNA transcription but also in mtDNA maintenance and mtDNA nucleoid formation (Kang and Hamasaki, 2005).
Therapeutic modulations of Sirt1 (Silent information regulator 1) and SOD2 have been suggested to offer potential for treatment of aged related neurodegenerative disorders connected with mitochondria alteration. Until now, neuroprotective strategies for AD are largely unsuccessful mainly because they are introduced too late at rather advance stage of the disease. The effect of several pharmacological compounds acting on Sirtuins and DNA-bound PARPs, both NAD-dependent families of enzymes, and on their role in different stages of AD, has not been fully elucidated. Little is known on the effect of these compounds at early stage of AD because diagnosis is too late. Therefore, more studies are needed to understand the dynamic and time-dependent molecular alterations of genes encoding proteins related to anti-oxidative defense, such as Sirts /PARPs /SODs, and mitochondria dynamics and function in animal models of AD at early stage of the disease. This subject was recently highlighted by Wang et al. (2020) and Yang et al. (2021). The mitochondria changes were also observed in lymphocytes of sporadic AD patients and the question arise if they could be an early marker for the diagnosis and prognosis of disease (Jörg et al. 2021). Recently, several pharmacological and natural compounds for treatment of AD also modulating expression and activity of Sirt1 have been tested in pre-clinical/clinical studies of human disorders (Manjula et al., 2020; Eckert et al 2020; Cummings et al., 2021).
Considering these deficiencies, this study used a transgenic AD mouse model to determine gene expression encoding proteins of anti-oxidative defense machinery, including SOD1 and mitochondrial SOD2, transcription profiles of NAD-dependent enzymes, and mRNA expression related to mitochondria dynamics, biogenesis and function in brain cortex of 3- and 6-month-old AD Tg mice as compared with corresponding age-matched controls (without transgene). The major goal here is to explore early target(s) for cytoprotection and promising therapeutic strategy in AD.