Heterozygous expression of the Alzheimer's disease-protective PLCγ2 P522R variant enhances Aβ clearance while preserving synapses.

Alzheimer Disease / genetics Amyloid beta-Peptides / genetics Humans Microglia / metabolism Phospholipase C gamma / genetics Synapses / metabolism
Alzheimer’s disease Microglia PLCG2 iPSC

Journal

Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402

Informations de publication

Date de publication:
27 Jul 2022
Historique:
received: 01 04 2022
accepted: 05 07 2022
revised: 29 06 2022
entrez: 27 7 2022
pubmed: 28 7 2022
medline: 30 7 2022
Statut: epublish

Résumé

A rare coding variant, P522R, in the phospholipase C gamma 2 (PLCG2) gene has been identified as protective against late-onset Alzheimer's disease (AD), but the mechanism is unknown. PLCG2 is exclusively expressed in microglia within the central nervous system, and altered microglial function has been implicated in the progression of AD. Healthy control hiPSCs were CRISPR edited to generate cells heterozygous and homozygous for the PLCG2 Heterozygous expression of the P522R variant resulted in increased microglial clearance of Aβ, while preserving synapses. This was associated with the upregulation of a number of genes, including the anti-inflammatory cytokine Il-10, and the synapse-linked CX3CR1, as well as alterations in mitochondrial function, and increased cellular motility. The protective capacity of PLCγ2 These findings suggest that PLCγ2

Sections du résumé

BACKGROUND BACKGROUND
A rare coding variant, P522R, in the phospholipase C gamma 2 (PLCG2) gene has been identified as protective against late-onset Alzheimer's disease (AD), but the mechanism is unknown. PLCG2 is exclusively expressed in microglia within the central nervous system, and altered microglial function has been implicated in the progression of AD.
METHODS METHODS
Healthy control hiPSCs were CRISPR edited to generate cells heterozygous and homozygous for the PLCG2
RESULTS RESULTS
Heterozygous expression of the P522R variant resulted in increased microglial clearance of Aβ, while preserving synapses. This was associated with the upregulation of a number of genes, including the anti-inflammatory cytokine Il-10, and the synapse-linked CX3CR1, as well as alterations in mitochondrial function, and increased cellular motility. The protective capacity of PLCγ2
CONCLUSION CONCLUSIONS
These findings suggest that PLCγ2

Identifiants

DOI: 10.1007/s00018-022-04473-1 PMID: 35895133 PMC: PMC9329165
pubmed: 35895133
doi: 10.1007/s00018-022-04473-1
pii: 10.1007/s00018-022-04473-1
pmc: PMC9329165
doi:

Substances chimiques

Amyloid beta-Peptides 0
PLCG2 protein, human EC 3.1.4.3
Phospholipase C gamma EC 3.1.4.3

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

453

Subventions

Organisme : National Centre for the Replacement, Refinement and Reduction of Animals in Research
ID : NC/S001506/1
Pays : United Kingdom

Informations de copyright

© 2022. The Author(s).

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Auteurs

Shiden Solomon (S)

Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. shiden.solomon@kcl.ac.uk.
UK Dementia Research Institute, King's College London, London, UK. shiden.solomon@kcl.ac.uk.

Nirmal Kumar Sampathkumar (NK)

Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
UK Dementia Research Institute, King's College London, London, UK.
Alzheimer's Research UK Oxford Drug Discovery Institute, Centre for Medicines Discovery, University of Oxford, Oxford, UK.

Ivo Carre (I)

Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
UK Dementia Research Institute, King's College London, London, UK.

Mrityunjoy Mondal (M)

Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
UK Dementia Research Institute, King's College London, London, UK.

George Chennell (G)

Wohl Cellular Imaging Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Anthony C Vernon (AC)

Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
MRC Centre for Neurodevelopmental Disorders, King's College London, London, UK.

Marc-David Ruepp (MD)

Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
UK Dementia Research Institute, King's College London, London, UK.

Jacqueline C Mitchell (JC)

Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. jacqueline.mitchell@kcl.ac.uk.
ORCID: 0000-0002-2677-398X

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Classifications MeSH

questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Démence › Maladie d'Alzheimer › Heterozygous expression of the Alzheimer's...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Peptides bêta-amyloïdes › Heterozygous expression of the Alzheimer's...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Heterozygous expression of the Alzheimer's...
questionsmedicales.fr › Cellules › Névroglie › Microglie › Heterozygous expression of the Alzheimer's...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Phosphoinositide Phospholipase C › Phospholipase C gamma › Heterozygous expression of the Alzheimer's...
questionsmedicales.fr › Cellules › Structures cellulaires › Membrane cellulaire › Structures de la membrane cellulaire › Jonctions intercellulaires › Synapses › Heterozygous expression of the Alzheimer's...