The role of PI3K/AKT pathway and its therapeutic possibility in Alzheimer's disease

Abstract

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Alzheimer's disease (AD) is the most common form of dementia. Although uncountable clinical trials have been done to develop the treatment of AD, there are a couple of drugs that can be used only for symptomatic treatment. Therefore, many studies based on the amyloid cascade hypothesis and the tauopathy hypothesis are still ongoing. After the failure of numerous huge Phase III clinical trials, arguments on those hypotheses have arisen and efforts to establish other possible therapeutic strategies based on diverse plausible mechanisms associated with AD have been done as well. One of the new therapeutic targets for AD is the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. In this review, questions on the two hypotheses, the definition of the PI3K/AKT pathway, the relationship between the pathway and AD, and the possibility of the modulation of the pathway as a new therapeutic strategy for AD will be discussed briefly.

A Mechanistic Evaluation of Antioxidant Nutraceuticals on Their Potential against Age-Associated Neurodegenerative Diseases

“…Overactivity of GSK-3β promoted tau hyperphosphorylation and amyloid plaque formation [ 214 ]. Aβ oligomers can also inhibit the PI3K/Akt pathway, activating GSK-3β, causing neurotoxicity [ 215 ]. Meanwhile, in PD, there is a significant decrease of Akt expression with the loss of dopaminergic neuron compared to control [ 216 ].…”

Molecular Targets Involved in the Neuroprotection Mediated by Terpenoids

“…Experimental evidence indicated that protein kinase B (Akt) is a pivotal survival signal molecule mediating anti-apoptosis and cell survival. Two mitochondrial proteins are phosphorylated following stimulation of mitochondrial Akt, the β-subunit of ATP synthase and GSK-3β, an important and well-known protein involved in the direct induction of tau phosphorylation in AD, which leads to cell death [34]. In addition, the survival phosphatidylinositol 3-kinase (PI3K/Akt) pathway modulates mammalian target of rapamycin (mTOR) kinase activity, which is also altered in neurodegenerative diseases accompanied by cognitive deficits (AD, PD) due to its implication in the regulation of a broad range of cellular processes, including survival, proliferation, growth, and migration of cells [34,35].…”

“…Two mitochondrial proteins are phosphorylated following stimulation of mitochondrial Akt, the β-subunit of ATP synthase and GSK-3β, an important and well-known protein involved in the direct induction of tau phosphorylation in AD, which leads to cell death [34]. In addition, the survival phosphatidylinositol 3-kinase (PI3K/Akt) pathway modulates mammalian target of rapamycin (mTOR) kinase activity, which is also altered in neurodegenerative diseases accompanied by cognitive deficits (AD, PD) due to its implication in the regulation of a broad range of cellular processes, including survival, proliferation, growth, and migration of cells [34,35]. The fact that the activation of mTOR is related to the presence of soluble Aβ and tau protein reveals the role of mTOR as one of the mechanisms involved in Aβ-induced toxicity in AD and indicates the potential of mTOR modulators as effective agents in the prevention of these pathologies [36].…”

“…Neuronal cytotoxicity induced by the abnormal deposition of proteins such as α-synuclein and amyloid beta-peptide (Aβ [25][26][27][28][29][30][31][32][33][34][35], in PD and AD experimental models, respectively, was protected by triptolide by acting as a potent autophagy inducer in neuronal cells [60,65]. Attenuation of immune-inflammatory responses of this diterpenoid on dendritic spines was observed after bilateral microinjection of aggregated beta-amyloid protein Ab1-40 into the hippocampus in a rat model of AD [66].…”

Current update in diverse diseases

“…In this article, he described the importance of the signaling pathway in AD. His review will improve readers' understanding on the relationship between the PI3K/Akt pathway and AD [3]. Fourth, Dr. Jung who is an expert on otology wrote cutting edge technologies on the otology field and reviewed their usefulness for patients with ear problems [4].…”