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Oxidative Stress, Endoplasmic Reticulum Stress and Apoptosis in the Pathology of Alzheimer’s Disease

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Abstract

Alzheimer’s disease (AD) accounts for a major statistic among the class of neurodegenerative diseases. A number of mechanisms have been identified in its pathogenesis and progression which include the amyloid beta (Aβ) aggregation, hyperphosphorylation of tau protein, oxidative stress, endoplasmic reticulum (ER) stress and apoptosis. These processes are interconnected and contribute significantly to the loss of neurons, brain mass and consequential memory loss and other cognitive difficulties. Oxidative stress in AD appears to be caused by excess of oxygen free radicals and extracellular Aβ deposits that cause local inflammatory processes and activate microglia, another possible source of reactive oxygen species (ROS). ER Stress describes the accumulation of misfolded and unfolded proteins as a result of physiological and pathological stimuli including high protein demand, toxins, inflammatory cytokines, and mutant protein expression that disturbs ER homeostasis. When compared to age-matched controls, postmortem brain tissues from AD patients showed elevated levels of ER stress markers, such as PERK, eIF2α, IRE1α, the chaperone Grp78, and the downstream mediator of cell death CHOP. Apoptosis is in charge of eliminating unnecessary and undesired cells to maintain good health. However, it has been demonstrated that a malfunctioning apoptotic pathway is a major factor in the development of certain neurological and immunological problems and diseases in people, including neurodegenerative diseases. This article highlights and discussed some of the experimentally established mechanisms through which these processes lead to the development as well as the exacerbation of AD.

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Abbreviations

AD:

Alzheimer’s disease

ROS:

Reactive Oxygen Species

DNA:

Deoxyribonucleic acid

ATP:

Adenosine Triphosphate

PUFA:

Polyunsaturated fatty acid

RNA:

Ribonucleic acid

CSF:

Cerebrospinal fluid

APP:

Amyloid processing protein

Aβ:

Amyliod beta

NFT:

Neurofibrilliary tangles

TBARS:

Thiobarbituric acid reactive substance

HNE:

Trans-4-hydroxy-2-nonenal

F2-IsoPs:

F2-isoprostanes

MCI:

Mild cognitive impairment

CSF:

Cerebrospinal fluid

3-NT:

3nitrotyrosine

SOD:

Superoxide dismutase

ABAD:

Aβ-binding alcohol dehydrogenase

NMDAR:

N-methyl-D-aspartate receptors

AMPA:

α-amino-3-hydroxy-5-methyl-4isoxa-zolepropionic acid

ER:

Endoplasmic reticulum

UPR:

Unfolded Protein Response

VDAC:

Voltage-dependent anion channel

LDH:

Lactate dehydrogenase

MDH:

Malate dehydrogenase

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

BCL-2:

B Cell lymphoma2

MAPK:

Mitogen activated protein kinase

BAD:

BCL2 associated agonist of cell death

APP/PS1:

amyloid precursor protein/presenilin 1

8OHdG:

8-hydroxy-2’-deoxyguanosine

NF-κB:

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

IRE1:

Inositol-requiring enzyme-1

PERK:

Protein kinase RNA-like endoplasmic reticulum kinase

ATF6:

activating transcription factor 6

XBP1:

X-box binding protein 1

ASK1:

Apoptosis signal regulating kinase 1

JNK:

c-Jun N-terminal protein kinase

TNF:

Tumor necrosis factor

TRAF2:

TNF Receptor Associated Factor 2

eIF2α:

eukaryotic initiation factor 2

GADD34:

growth arrest and DNA damage-inducible protein

Atf-4:

Activating transcription factor 4

uORF:

upstream open reading frames

BZIP:

basic leucine-zipper (bZIP) proteins

CHOP:

C/EBP homologous protein

ATF6:

Activating transcription factor 6

ERAD:

Endoplasmic reticulum–associated protein degradation

BACE1:

β-site APP cleaving enzyme-1

CREB:

cAMP response element-binding protein

STZ:

Streptozotocin

OHC:

Organotypic hippocampal slice cultures

Bax:

Bcl-2-associated X protein

PAR-4:

Prostate apoptosis response

CARD:

Caspase recruitment domain

DED:

Death effector domain

SMAC/direct:

IAP binding protein with low pI (DIABLO),

HTRA:

high temperature requirement A (serine peptidase 2)

APAF-1:

Apoptotic protease-activating factor 1

CAD:

Caspase-activated DNase

AIF:

Apoptosis-inducing factor

CTL:

Cytotoxic T lymphocytes

BAK:

Bcl-2 antagonist killer 1

BIM:

Bcl-2 Interacting Mediator of cell death

TRAIL:

Tumor necrosis factor-related apoptosis-inducing ligand

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All authors contributed equally to the writing, proof reading, correction and preparation of the draft and final copy of the manuscript.

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  1. Department of Biochemistry Afe Babalola University, PMB 5454, Ado-Ekiti, Nigeria

    Bidemi Emmanuel Ekundayo, Tajudeen Olabisi Obafemi, Olusola Bolaji Adewale & Babatunji Emmanuel Oyinloye

  2. Department of Medical Biochemistry Afe Babalola University, PMB 5454, Ado-Ekiti, Nigeria

    Blessing Ariyo Obafemi

  3. Biotechnology and Structural Biology (BSB) Group, Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa, 3886, South Africa

    Babatunji Emmanuel Oyinloye

  4. Department of Chemistry Education Federal University, Oye-Ekiti, Nigeria

    Stella Kemilola Ekundayo

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Ekundayo, B.E., Obafemi, T.O., Adewale, O.B. et al. Oxidative Stress, Endoplasmic Reticulum Stress and Apoptosis in the Pathology of Alzheimer’s Disease. Cell Biochem Biophys (2024). https://doi.org/10.1007/s12013-024-01248-2

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