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Regulated cell death and its role in Alzheimer’s disease and amyotrophic lateral sclerosis

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Abstract

Despite considerable research efforts, it is still not clear which mechanisms underlie neuronal cell death in neurodegenerative diseases. During the last 20 years, multiple pathways have been identified that can execute regulated cell death (RCD). Among these RCD pathways, apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy-related cell death, and lysosome-dependent cell death have been intensively investigated. Although RCD consists of numerous individual pathways, multiple common proteins have been identified that allow shifting from one cell death pathway to another. Another layer of complexity is added by mechanisms such as the endosomal machinery, able to regulate the activation of some RCD pathways, preventing cell death. In addition, restricted axonal degeneration and synaptic pruning can occur as a result of RCD activation without loss of the cell body. RCD plays a complex role in neurodegenerative processes, varying across different disorders. It has been shown that RCD is differentially involved in Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS), among the most common neurodegenerative diseases. In AD, neuronal loss is associated with the activation of not only necroptosis, but also pyroptosis. In ALS, on the other hand, motor neuron death is not linked to canonical necroptosis, whereas pyroptosis pathway activation is seen in white matter microglia. Despite these differences in the activation of RCD pathways in AD and ALS, the accumulation of protein aggregates immunoreactive for p62/SQSTM1 (sequestosome 1) is a common event in both diseases and many other neurodegenerative disorders. In this review, we describe the major RCD pathways with clear activation in AD and ALS, the main interactions between these pathways, as well as their differential and similar involvement in these disorders. Finally, we will discuss targeting RCD as an innovative therapeutic concept for neurodegenerative diseases, such as AD and ALS. Considering that the execution of RCD or “cellular suicide” represents the final stage in neurodegeneration, it seems crucial to prevent neuronal death in patients by targeting RCD. This would offer valuable time to address upstream events in the pathological cascade by keeping the neurons alive.

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All relevant novel data not covered by the reviewed studies of this review article are available in this manuscript, online supplementary information or upon reasonable request.

Abbreviations

4HB:

Four-helix bundle

ACSL4:

Acyl-CoA synthetase long-chain family member 4

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

Apaf-1:

Apoptotic activating factor 1

ASC:

Apoptosis-associated speck-like protein containing a caspase recruitment domain

ATG14L:

Yeast autophagy-related protein 14-like

ATG4/5/7/8/12/16:

Yeast autophagy-related protein4/5/7/8/12/16

Aβ:

Amyloid β peptide

Bcl-2:

B-cell lymphoma 2

CAA:

Cerebral amyloid angiopathy

cFLIP:

Cellular FLICE-like inhibitory protein

CHMP2B:

Charged multivesicular body protein 2B

cIAP1/2:

Cellular inhibitor of apoptosis protein 1/2

cleaved GSDMD:

GSDMD cleaved at Asp275 leading to the formation of GSDMD-NT, indicative of pyroptosis activation

Cyt c:

Cytochrome c

DAMP:

Damage-associated molecular pattern

DISC:

Death-inducing signaling complex

DPR:

Dipeptide repeat protein

ER:

Endoplasmic reticulum

ESCRT:

Endosomal sorting complexes required for transport

EV:

Extracellular vesicle

FADD:

FAS-associated death domain

FAS:

Fas cell surface death receptor

FPN:

Ferroportin

FTLD-TDP:

Frontotemporal lobar degeneration with TPD-43-immunoreactive pathology

FUS:

Fused in sarcoma

GA:

DPR poly-glycine–alanine

GP:

DPR poly-glycine–proline

GPX4:

Glutathione peroxidase 4

GR:

DPR poly-glycine–arginine

GSDMD:

Gasdermin D

GSDMD-NT:

N-terminal fragment of GSDMD

GSH:

Glutathione

GVD:

Granulovacuolar degeneration

HAMP:

Homeostasis-altering molecular process

IL-18:

Interleukin 18

IL-1β:

Interleukin-1β

LATE-NC:

Limbic-predominant age-related TDP-43 encephalopathy neuropathological changes

LCD:

Lysosome-dependent cell death

LPS:

Lipopolysaccharide

LUBAC:

Linear ubiquitin chain assembly complex

MAP1LC3 or LC3:

Microtubule-associated protein 1 light chain 3

MAPK:

Mitogen-activated protein kinase

MLKL:

Mixed lineage kinase domain-like protein

MOMP:

Mitochondrial outer membrane permeabilization

MTL:

Medial temporal lobe

NF-κB:

Nuclear factor-κB

NFT:

Neurofibrillary tangle

NLR:

NOD-like receptor

NLRP3:

Nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3

NOS:

Not otherwise specified

OPTN:

Optineurin

p62/SQSTM1:

Sequestosome 1

PA:

DPR poly-proline–alanine

PAMP:

Pathogen-associated molecular pattern

PE:

Phosphatidylethanolamine

PR:

DPR poly-proline–arginine

PRR:

Pattern recognition receptor

p-τ:

Phosphorylated tau protein

RCD:

Regulated cell death

RHIM:

RIP homotypic interaction motif

RIPK1:

Receptor-interacting serine/threonine protein kinase 1

RIPK3:

Receptor-interacting serine/threonine protein kinase 3

ROS:

Reactive oxygen species

SOD1:

Superoxide dismutase 1

TBK1:

TANK-binding kinase 1

TDP-43:

TAR DNA-binding protein 43

TLR:

Toll-like receptors

TNF:

Tumor necrosis factor

TNFR1:

TNF receptor superfamily member 1A

TRADD:

TNFR1‑associated death domain

TRAF2:

TNFR-associated factor 2

TRAILR1:

TNF receptor superfamily member 10a

TRAILR2:

TNF receptor superfamily member 10b

ULK:

UNC-51-like kinase complex

Vps15:

Class III PI-3 kinase vacuolar protein sorting 15

Vps34:

Class III PI-3 kinase vacuolar protein sorting 34

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Acknowledgements

The authors thank Ms. Simona Ospitalieri and Mrs. Alicja Ronisz for technical help in producing the histopathological specimen for the neuropathological images depicted here.

Funding

This study was funded by Fonds Wetenschappelijk Onderzoek (FWO, Belgium): G0F8516N, G065721N (DRT); KU Leuven internal funds (Belgium): C14-17–107, C14/22/132 (DRT), DB/20/007/BM (SM); Stichting Alzheimer Onderzoek, Belgium: SAO/FRA 2023/0009 (DRT); and Alzheimer’s Association (USA): 22-AAIIA-963171 (DRT).

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  1. Laboratory for Neuropathology, Department of Imaging and Pathology and Leuven Brain Institute (LBI), KU-Leuven, Herestraat 49, 3000, Leuven, Belgium

    Dietmar Rudolf Thal, Klara Gawor & Sebastiaan Moonen

  2. Department of Pathology, University Hospitals Leuven, Leuven, Belgium

    Dietmar Rudolf Thal

  3. Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, KU Leuven, Leuven Brain Institute (LBI), Leuven, Belgium

    Sebastiaan Moonen

  4. Center for Brain & Disease Research, VIB, Leuven, Belgium

    Sebastiaan Moonen

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Correspondence to Dietmar Rudolf Thal.

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DRT received consultant speaker honorary from Biogen (USA), travel reimbursement from GE-Healthcare (UK) and UCB (Belgium), and collaborated with Novartis Pharma AG (Switzerland), Probiodrug (Germany), GE-Healthcare (UK), and Janssen Pharmaceutical Companies (Belgium). DRT is a member of Acta Neuropathologica editorial board. He was not involved in the assessment or decision-making process for this manuscript.

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Thal, D.R., Gawor, K. & Moonen, S. Regulated cell death and its role in Alzheimer’s disease and amyotrophic lateral sclerosis. Acta Neuropathol 147, 69 (2024). https://doi.org/10.1007/s00401-024-02722-0

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