Monitoring of Neuronal Loss in the Hippocampus of Aβ-Injected Rat: Autophagy, Mitophagy, and Mitochondrial Biogenesis Stand Against Apoptosis

Abstract

In the present study, we tried to answer the following questions: which kind of defense pathways are activated after Aβ insult? How defense systems react against noxious effects of Aβ and whether they are able to deal against apoptosis or not? So, we traced some molecular pathways including autophagy, mitophagy, and mitochondrial biogenesis before reaching to the endpoint of apoptosis. Besides, we measured the function of mitochondria after injection of Aβ (1-42) in CA1 area of hippocampus as a model of Alzheimer's disease (AD). Based on our data, autophagy markers reached to their maximum level and returned to the control level as apoptotic markers started to increase. As a specialized form of autophagy, mitophagy markers followed the trend of autophagy markers. Whereas mitochondrial dynamic processes shifted toward fission, mitochondrial biogenesis was severely affected by Aβ and significantly decreased. Alongside suppression of mitochondrial biogenesis, activity of specific enzymes involved in antioxidant defense system, electron transport chain, and tricarboxylic acid cycle (TCA) decreased in response to the Aβ. Activity of antioxidant enzymes increased at first and then decreased significantly compared to the control. TCA enzymes aconitase and malate dehydrogenase activities reduced immediately while citrate synthase and fumarase activities did not change. Based on our finding, monitoring of the master molecules of intracellular cascades and determining their trends before the destructive function of Aβ could be the target of therapeutic issues for AD.

Inhibition of Akt Phosphorylation Diminishes Mitochondrial Biogenesis Regulators, Tricarboxylic Acid Cycle Activity and Exacerbates Recognition Memory Deficit in Rat Model of Alzheimer’s Disease

“…Accordingly, inhibition of Akt phosphorylation can explain decreased PGC-1a level in 3-MAadministrated rats with or without Ab injection. Since, as we reported previously (Shaerzadeh et al 2014), Ab significantly reduces PGC-1a in hippocampal neurons, it seems that deleterious effect of Ab and 3-MA on PGC-1a could be added to each other. As mentioned above, PGC1a binds to the cognate promoter of several genes that are involved in mitochondrial biogenesis like NRF-1, Tfam, and etc.…”

“…The end products of TCA cycle are reducing equivalents in the form of NADH and flavin adenine dinucleotide (FADH 2 ) as the first step of oxygen-dependent energy production. Our previous study indicated that activities of Aconitase and MDH enzymes severely decrease in the presence of Ab (Shaerzadeh et al 2014). In the present study, our data from biochemical tests further demonstrated that the activities of three enzymes of TCA cycle including Aconitase, a-KGDH, and MDH decreased when using 3-MA with or without Ab injection.…”

“…Therefore, even the slightest change due to presence of Ab could affect cell physiology and homeostasis in this situation. In this manner, our previous study displayed that mitochondrial biogenesis markers and specific enzymes of mitochondria are severely influenced by Ab (Shaerzadeh et al 2014). 3-Methyladenine (3-MA) is well known as the specific inhibitor of autophagy that persistently inhibits class I PI3K, located at the upstream of PI3K/Akt signaling pathway (Wu et al 2010).…”

Aβ25–35 Suppresses Mitochondrial Biogenesis in Primary Hippocampal Neurons

“…Our results also showed that mRNA levels and protein levels of mitochondrial biogenesis factors (PGC-1a, NRF 1, NRF 2, and Tfam) were reduced after 24-h incubation with Ab25-35. Similarly, intrahippocampal injection of Ab1-42 in rats resulted in decreases in PGC-1a, NRF 1, and Tfam (Shaerzadeh et al 2014). Taken together, these findings indicate that Ab suppresses mitochondrial biogenesis both in vitro and in vivo.…”

“…Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in AD (Sheng et al 2012). Moreover, mitochondrial biogenesis is severely affected and significantly decreases after injection of Ab in hippocampal CA1 area of rats (Shaerzadeh et al 2014). However, whether Ab suppresses mitochondrial biogenesis in primary hippocampal neurons remains unclear.…”