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The PI3K/Akt signaling axis in Alzheimer’s disease: a valuable target to stimulate or suppress?

  • Mini Review
  • Published:
Cell Stress and Chaperones Aims and scope

Abstract

Among the long list of age-related complications, Alzheimer’s disease (AD) has the most dreadful impact on the quality of life due to its devastating effects on memory and cognitive abilities. Although a plausible correlation between the phosphatidylinositol 3-kinase (PI3K) signaling and different processes involved in neurodegeneration has been evidenced, few articles reviewed the task. The current review aims to unravel the mechanisms by which the PI3K pathway plays pro-survival roles in normal conditions, and also to discuss the original data obtained from international research laboratories on this topic. Responses to questions on how alterations of the PI3K/Akt signaling pathway affect Tau phosphorylation and the amyloid cascade are given. In addition, we provide a general overview of the association between oxidative stress, neuroinflammation, alterations of insulin signaling, and altered autophagy with aberrant activation of this axis in the AD brain. The last section provides a special focus on the therapeutic possibility of the PI3K/Akt/mTOR modulators, either categorized as chemicals or herbals, in AD. In conclusion, determining the correct timing for the administration of the drugs seems to be one of the most important factors in the success of these agents. Also, the role of the PI3K/Akt signaling axis in the progression or repression of AD widely depends on the context of the cells; generally speaking, while PI3K/Akt activation in neurons and neural stem cells is favorable, its activation in microglia cells may be harmful.

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Abbreviations

AD:

Alzheimer’s disease

ADDLs:

Aβ-derived diffusible ligands

APP:

Amyloid precursor protein

ARE:

Antioxidant response elements

Aβ:

Amyloid β

BDNF:

Brain-derived neurotrophic factor

CaMKII:

Ca2+/calmodulin-dependent kinase II

CK2:

Casein kinase 2

CNS:

Central nervous system

COX-1:

Cyclooxygenase-1

COX-2:

Cyclooxygenase-2

CXCL12:

C-X-C motif chemokine 12

DNA:

Deoxyribonucleic acid

eIF2-α:

Eukaryotic translation initiation factor-alpha

FGF:

Fibroblast growth factor

GABA:

γ-Aminobutyric acid

GSK-3β:

Glycogen synthase kinase-3β

HMK:

Halomethylketones 6

IGF1:

Insulin-like growth factor-1

IL1-β:

Interleukin 1 beta

iNOS:

Inducible nitric oxide synthase

IRS:

Insulin receptor substrate

LTP:

Long-term potentiation

mTOR:

Mammalian target of rapamycin

NFTs:

Neurofibrillary tangles

NF-κB:

Nuclear factor kappa light chain enhancer of activated B cells

NMDA:

N-methyl-D-aspartate

Nrf2:

Nuclear factor erythroid 2

NRG1:

Neuregulin-1

NSCs:

Neurons and neural stem cells

PHF/SF:

Paired helical/straight filaments

PI3K:

Phosphatidyl inositol 3-kinase

PIP2:

Phosphotidylinositol 4,5-Bisphosphate

PIP3:

Phosphatidylinositol (3,4,5)-trisphosphate

PTEN:

Phosphatase and tensin homolog

PTMs:

Post-translational modifications

ROS:

Reactive oxygen specious

SH2:

Src homology 2

SODs:

Superoxide dismutase

TDZD:

Thiadiazolidinones 5

TGF-β:

Transforming growth factor β

TLR4:

Toll-like receptor 4

TNF-α:

Tumor necrosis factor alpha

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Acknowledgements

The authors would like to express their gratitude to Shahid Beheshti University of Medical Sciences (Tehran, Iran) for supporting this study.

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Authors and Affiliations

  1. Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Elham Razani, Atieh Pourbagheri-Sigaroodi, Ava Safaroghli-Azar & Davood Bashash

  2. Department of Neurology, School of Medicine, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Anahita Zoghi

  3. Institute of Neuroscience, Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain

    Mahsa Shanaki-Bavarsad

  4. Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain

    Mahsa Shanaki-Bavarsad

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  1. Elham Razani
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Correspondence to Davood Bashash.

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Razani, E., Pourbagheri-Sigaroodi, A., Safaroghli-Azar, A. et al. The PI3K/Akt signaling axis in Alzheimer’s disease: a valuable target to stimulate or suppress?. Cell Stress and Chaperones 26, 871–887 (2021). https://doi.org/10.1007/s12192-021-01231-3

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  • DOI: https://doi.org/10.1007/s12192-021-01231-3

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