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Apoptotic Pathways and Alzheimer’s Disease: Probing Therapeutic Potential

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Abstract

Apoptosis is an intrinsic biochemical, cellular process that regulates cell death and is crucial for cell survival, cellular homeostasis, and maintaining the optimum functional status. Apoptosis in a predetermined and programmed manner regulates several molecular events, including cell turnover, embryonic development, and immune system functions but may be the exclusive contributor to several disorders, including neurodegenerative manifestations, when it functions in an aberrant and disorganized manner. Alzheimer’s disease (AD) is a fatal, chronic neurodegenerative disorder where apoptosis has a compelling and divergent role. The well-characterized pathological features of AD, including extracellular plaques of amyloid-beta, intracellular hyperphosphorylated tangles of tau protein (NFTs), inflammation, mitochondrial dysfunction, oxidative stress, and excitotoxic cell death, also instigate an abnormal apoptotic cascade in susceptible brain regions (cerebral cortex, hippocampus). The apoptotic players in these regions affect cellular organelles (mitochondria and endoplasmic reticulum), interact with trophic factors, and several pathways, including PI3K/AKT, JNK, MAPK, mTOR signalling. This dysregulated apoptotic cascade end with an abnormal neuronal loss which is a primary event that may precede the other events of AD progression and correlates well with the degree of dementia. The present review provides insight into the diverse and versatile apoptotic mechanisms that are indispensable for neuronal survival and constitute an integral part of the pathological progression of AD. Identification of potential targets (restoring apoptotic and antiapoptotic balance, caspases, TRADD, RIPK1, FADD, TNFα, etc.) may be valuable and advantageous to decide the fate of neurons and to develop potential therapeutics for treatment of AD.

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Abbreviations

AIF:

Apoptosis-Inducing Factor

AMPK:

AMP-Activated Protein Kinase

Apaf1:

Apoptotic Protease Activating Factor 1

APP:

βAmyloid Precursor Protein

ATF-6:

Activating Transcription Factor-6

BAX:

Bcl-2 Associated X Protein

CREB:

cAMP Response Element-Binding Protein

ERK:

Extracellular Signalregulated Protein Kinase

FADD:

Fas Associated Death Domain

FKH/FOXO:

factor Forkhead/Forkhead Box Transcription Factors

GSK3B:

Glycogen Synthase Kinase 3β

IFN-γ:

Interferon-Gamma

IRE1:

Inositol-Requiring Enzyme-1

JAK:

Janus Kinase

JNK:

c-Jun N-Terminal Kinase

MAPK:

A Mitogen-Activated Protein Kinase

mTOR:

Mammalian Target of Rapamycin

NFKB:

Nuclear Factor Kappa B

PARP1:

Poly (ADP-Ribose) Polymerase

PERK:

Pancreatic ER Kinase

PI3K:

Phosphatidylinositol-3-Kinase

RIP:

Receptor Interacting Protein

STAT:

Signal Transducer and Activator of Transcription

TACE:

TNF-α Converting Enzyme

TAT–TIJIP:

Tat Cell Transporter Sequence–Truncated Inhibitor of JNK Interacting Protein

TNF-α:

Tumor Necrosis Factor Alpha

TRADD:

TNF Receptor Associated Death Domain

TSC1:

Tuberous Sclerosis Protein 1

WNT:

Wingless-Related Integration

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Acknowledgements

The authors are grateful to the Chitkara College of Pharmacy, Chitkara University, Rajpura, Patiala, Punjab, India for providing the necessary facilities to carry out the research work.

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Authors and Affiliations

  1. Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India

    Vivek Kumar Sharma, Thakur Gurjeet Singh, Shareen Singh, Nikhil Garg & Sonia Dhiman

  2. Government College of Pharmacy, Rohru, District Shimla, Himachal Pradesh, 171207, India

    Vivek Kumar Sharma

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Conceptualization: Conceived and designed the experiments: TGS. Analyzed the data: VKS, NG. Wrote the manuscript: VKS, SS. Visualization: VKS, TGS Editing of the Manuscript: VKS, SS, TGS Critically reviewed the article: TGS, SD. Supervision: TGS. All authors read and approved the final manuscript.

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Sharma, V.K., Singh, T.G., Singh, S. et al. Apoptotic Pathways and Alzheimer’s Disease: Probing Therapeutic Potential. Neurochem Res 46, 3103–3122 (2021). https://doi.org/10.1007/s11064-021-03418-7

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