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Implications of Phosphoinositide 3-Kinase-Akt (PI3K-Akt) Pathway in the Pathogenesis of Alzheimer’s Disease

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Abstract

Alzheimer’s disease (AD) is the foremost type of dementia that afflicts considerable morbidity and mortality in aged population. Several transcription molecules, pathways, and molecular mechanisms such as oxidative stress, inflammation, autophagy, and immune system interact in a multifaceted way that disrupt physiological processes (cell growth, differentiation, survival, lipid and energy metabolism, endocytosis) leading to apoptosis, tauopathy, β-amyloidopathy, neuron, and synapse loss, which play an important role in AD pathophysiology. Despite of stupendous advancements in pathogenic mechanisms, treatment of AD is still a nightmare in the field of medicine. There is compelling urgency to find not only symptomatic but effective disease-modifying therapies. Recently, phosphoinositide 3-kinase (PI3K) and Akt are identified as a pathway triggered by diverse stimuli, including insulin, growth factors, cytokines, and cellular stress, that link amyloid-β, neurofibrillary tangles, and brain atrophy. The present review aims to explore and analyze the role of PI3K-Akt pathway in AD and agents which may modulate Akt and have therapeutic prospects in AD. The literature was researched using keywords “PI3K-Akt” and “Alzheimer’s disease” from PubMed, Web of Science, Bentham, Science Direct, Springer Nature, Scopus, and Google Scholar databases including books. Articles published from 1992 to 2021 were prioritized and analyzed for their strengths and limitations, and most appropriate ones were selected for the purpose of review. PI3K-Akt pathway regulates various biological processes such as cell proliferation, motility, growth, survival, and metabolic functions, and inhibits many neurotoxic mechanisms. Furthermore, experimental data indicate that PI3K-Akt signaling might be an important therapeutic target in treatment of AD.

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Abbreviations

ACh:

Acetylcholine

AChE:

Acetylcholinesterase

AD:

Alzheimer’s disease

AGE:

Advanced glycation end-products

APOE:

Apolipoprotein E

APP:

Amyloid precursor protein

Aβ :

Amyloid-beta

BACE-1:

Beta-site amyloid precursor protein cleaving enzyme 1 (β-secretase)

Bad:

Bcl-2-associated death promoter (BAD) protein

Bax:

Bcl-2-associated X protein

BCAP:

B-cell adaptor protein for phosphoinositide 3-kinase

Bcl-2:

B-cell lymphoma 2

BCR (BR):

B cell receptor

Bcl-XL :

B cell lymphoma-extra large

BDNF:

Brain-derived neurotrophic factor

Bim:

Bcl-2-Like Protein 11

CA:

Cornu Ammonis

CD:

Complement derived

ChAT:

Choline-acetyl transferase

CREB:

CAMP response element binding protein

CRMP:

Collapsin response mediator protein

DNA:

Deoxyribonucleic acid

4EBP1:

Eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1

EGF:

Epidermal growth factor

eNOS:

Endothelial nitric oxide synthase

ERK:

Extracellular signal-regulated kinase

FoxO1:

Forkhead box protein O1

FYVE:

Fab 1, YOTB, Vac 1, EEA1

GAB-1:

GRB2-associated-binding protein 1

GABA:

Gamma amino butyric acid

GLUT:

Glucose transporter

GPCR:

G-protein coupled receptor

GSK-3:

Glycogen synthase kinse-3

HECT:

E3 ligases of the homologous to the E6AP carboxyl terminus

HIF:

Hypoxia inducible factor

IL:

Interleukin

iNOS:

Inducible nitric oxide synthase

IR:

Insulin receptor

IRS:

Insulin receptor substrate

JAK:

Janus kinases

JNK:

C-Jun (ju-nana) N-terminal kinases

LTβR:

Lymphotoxin-β receptor

LTD:

Long-term depression

LTP:

Long-term potentiation

mAChR:

Muscarinic acetylcholine receptors

MAPK:

Mitogen-activated protein kinase

MCI:

Mild cognitive impairment

Mcl-1:

Myeloid cell leukemia 1

MDA:

Malondialdehyde

mTOR:

Mammalian target of rapamycin

nAChR:

Nicotinic acetylcholine receptors

NEMO:

NFκB essential modulator

NFTs:

Neurofibrillary tangles

NFκB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NGF:

Nerve growth factor

NMDA:

N-Methyl-D-aspartate

nNOS:

Neuronal nitric oxide synthase

NO:

Nitric oxide

NOX family:

NADPH oxidase [NOX2/gp91(phox)] family

Nrf2:

Nuclear factor (erythroid-derived 2)-like 2

p-Akt:

Phosphorylated Akt

PAMPs:

Pathogen-associated microbial patterns

PARP:

Poly ADP ribose polymerase

PDGF:

Platelet-derived growth factor

PDK1:

3-Phosphoinositide-dependent protein kinase-1

p-GSK-3:

Phosphorylated GSK-3

PH-Domain:

Pleckstrin homology domain

PHFs:

Paired helical filaments

PI3K:

Phosphoinositide 3-kinase

PIs:

Phosphoinositide

PP2A:

Protein phosphatase 2A

PS:

Presenilin

PTEN:

Phosphatase and tensin homolog

RAGE:

Receptors for advanced glycation end-products

Rheb:

Ras homolog enriched in brain

Rho-kinase:

Rho-associated coiled-coil-containing protein kinase

ROS:

Reactive oxygen species

RTK:

Receptor tyrosine kinase

S6K1:

S6 kinase 1

Ser:

Serine (S)

SHIP:

Src-homology 2 containing inositol (poly)phosphate-5-phosphatases

Thr:

Threonine (T)

t1/2 :

Half-life

TLR:

Toll-like receptor

TNFR:

Tumor necrosis factor receptor

TNF-α :

Tumor necrosis factor-α

TRAF6:

Tumor necrosis factor receptor (TNFR)-associated factor 6

TSC:

Tuberous sclerosis complex

Vps 34:

Vacuolar protein-sorting defective 34

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Acknowledgements

The authors are thankful to I.K.G. Punjab Technical University, Jalandhar (Punjab) and Amar Shaheed Baba Ajit Singh Jujhar Singh Memorial College of Pharmacy, Bela, Ropar (Punjab).

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  1. Chitkara College of Pharmacy, Chitkara University, Punjab, India

    Manish Kumar

  2. Department of Pharmaceutical Sciences, Chaudhary Bansi Lal University (CBLU), Bhiwani, Haryana, 127021, India

    Nitin Bansal

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MK and NB wrote and critically revised the manuscript.

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Kumar, M., Bansal, N. Implications of Phosphoinositide 3-Kinase-Akt (PI3K-Akt) Pathway in the Pathogenesis of Alzheimer’s Disease. Mol Neurobiol 59, 354–385 (2022). https://doi.org/10.1007/s12035-021-02611-7

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