Cellular and molecular neurobiology, 2014-11, Vol.34 (8), p.1223-1233
2014
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- Autor(en) / Beteiligte
- Titel
- Inhibition of Akt Phosphorylation Diminishes Mitochondrial Biogenesis Regulators, Tricarboxylic Acid Cycle Activity and Exacerbates Recognition Memory Deficit in Rat Model of Alzheimer’s Disease
- Ist Teil von
- Cellular and molecular neurobiology, 2014-11, Vol.34 (8), p.1223-1233
- Ort / Verlag
- Boston: Springer US
- Erscheinungsjahr
- 2014
- Quelle
- SpringerLink
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0272-4340eISSN: 1573-6830DOI: 10.1007/s10571-014-0099-9Titel-ID: cdi_proquest_miscellaneous_1635027379
- Format
- –
- Schlagworte
- Adenine - administration & dosage, Adenine - analogs & derivatives, Adenine - pharmacology, Alzheimer Disease - complications, Alzheimer Disease - enzymology, Alzheimer Disease - physiopathology, AMP-Activated Protein Kinases - metabolism, Amyloid beta-Peptides - administration & dosage, Animals, Biomedical and Life Sciences, Biomedicine, Cell Biology, Citric Acid Cycle - drug effects, Cyclic AMP Response Element-Binding Protein - metabolism, Discrimination (Psychology) - drug effects, Disease Models, Animal, Down-Regulation - drug effects, Exploratory Behavior - drug effects, Hippocampus - drug effects, Hippocampus - enzymology, Hippocampus - physiopathology, Injections, Intraventricular, Male, Memory Disorders - enzymology, Memory Disorders - pathology, Memory Disorders - physiopathology, Mitochondria - drug effects, Mitochondria - metabolism, Neurobiology, Neurosciences, Original Research, Phosphorylation - drug effects, Proto-Oncogene Proteins c-akt - antagonists & inhibitors, Proto-Oncogene Proteins c-akt - metabolism, Pyruvate Dehydrogenase Complex - metabolism, Rats, Wistar, Recognition (Psychology) - drug effects