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

Abstract

3-Methyladenine (3-MA), as a PI3K inhibitor, is widely used for inhibition of autophagy. Inhibition of PI3K class I leads to inhibition of Akt phosphorylation, a central molecule involved in diverse arrays of intracellular cascades in nervous system. Accordingly, in the present study, we aimed to determine the alterations of specific mitochondrial biogenesis markers and mitochondrial function in 3-MA-injected rats following amyloid beta (Aβ) insult. Our data revealed that inhibition of Akt phosphorylation downregulates master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Our data also showed that decrease in PGC-1α level presumably is due to decrease in the phosphorylation of cAMP-response element binding and AMP-activated kinase, two upstream activators of PGC-1α. As a consequence, the level of some mitochondrial biogenesis factors including nuclear respiratory factor-1, mitochondrial transcription factor A, and Cytochrome c decreased significantly. Also, activities of tricarboxylic acid cycle (TCA) enzymes such as Aconitase, a-ketoglutarate dehydrogenase, and malate dehydrogenase reduced in the presence of 3-MA with or without Aβ insult. Decrease in mitochondrial biogenesis factors and TCA enzyme activity in the rats receiving 3-MA and Aβ were more compared to the rats that received either alone; indicating the additive destructive effects of these two agents. In agreement with our molecular results, data obtained from behavioral test (using novel objective recognition test) indicated that inhibition of Akt phosphorylation with or without Aβ injection impaired novel recognition (non-spatial) memory. Our results suggest that 3-MA amplified deleterious effects of Aβ by targeting central molecule Akt.

Mineral trioxide aggregate‐induced AMPK activation stimulates odontoblastic differentiation of human dental pulp cells

“…This suggests that AMPK activation is associated with autophagy induction, which is involved in the process of MTAinduced odontoblastic differentiation of dental pulp cells. A similar result reported that p-AMPK levels declined in the 3MA-administrated rat model of Alzheimer leads to reduced neurogenesis and induced memory deficit (Shaerzadeh et al 2014 Reparative dentine formation is an important process in the recovery of the pulp-dentine complex (Goldberg & Smith 2004, Charadram et al 2012. When injuries of dentine occur, subjacent HDPCs are attracted to the damaged site and undergo odontogenic differentiation to form new dentine.…”

“…A similar result reported that p‐AMPK levels declined in the 3MA‐administrated rat model of Alzheimer leads to reduced neurogenesis and induced memory deficit (Shaerzadeh et al . 2014). Additionally, mTOR phosphorylation and ULK1 phosphorylation at Ser 757 were moderately decreased, but ULK1 phosphorylation at Ser 317 was largely increased in MTA‐treated cells.…”

Sevoflurane-induced memory impairment in the postnatal developing mouse brain

“…PI3K can then phosphorylate Akt/PKB. Inhibition of Akt phosphorylation exacerbates memory deficits in a rat model of Alzheimer's disease ( 39 ). Thus, activation of PI3K may be inhibited by sevoflurane and thereby decrease levels of phosphorylated Akt, as well as inhibit cleavage of pro-BDNF.…”

The role of mitochondrial disturbances in Alzheimer, Parkinson and Huntington diseases

“…These divergent findings may reflect different stages of AD progression. In an animal model of AD, it was demonstrated that the inhibition of mitochondrial biogenesis regulators is associated with the inhibition of Akt phosphorylation [166]. In the same mouse model, Zhang et al [167] reported that neural stem cell transplantation enhances mitochondrial biogenesis.…”