Differential interaction with TREM2 modulates microglial uptake of modified Aβ species

Autor: Hannah Scheiblich, Peter St George-Hyslop, Jochen Walter, Nàdia Villacampa, Michael T. Heneka, Samira Parhizkar, Pranav Joshi, Seema Qamar, Sandra Theil, Florian Riffel, Kanayo Satoh, Paul E. Fraser, Christian Haass, Masahiro Enomoto, Sathish Kumar
Přispěvatelé: Joshi, Pranav [0000-0002-1153-0440], Riffel, Florian [0000-0001-8594-100X], Villacampa, Nàdia [0000-0001-6513-0250], Kumar, Sathish [0000-0002-2792-7047], Parhizkar, Samira [0000-0001-5807-190X], Walter, Jochen [0000-0002-4678-2912], Apollo - University of Cambridge Repository
Rok vydání: 2021
Předmět:
Genetically modified mouse
FTD mutation
Phagocytosis
metabolism [Amyloid beta-Peptides]
genetics [Alzheimer Disease]
Mice
Transgenic
Biology
metabolism [Microglia]
03 medical and health sciences
Cellular and Molecular Neuroscience
Amyloid beta-Protein Precursor
Mice
0302 clinical medicine
genetics [Membrane Glycoproteins]
Alzheimer Disease
metabolism [Amyloid beta-Protein Precursor]
medicine
Amyloid precursor protein
TREM2
genetics [Receptors
Immunologic]
Animals
ddc:610
Receptors
Immunologic
Receptor
030304 developmental biology
0303 health sciences
Amyloid beta-Peptides
Membrane Glycoproteins
Microglia
phosphorylation
metabolism [Receptors
Immunologic]
Alzheimer's disease
3. Good health
Cell biology
Disease Models
Animal
medicine.anatomical_structure
Neurology
post-translational modification
genetics [Amyloid beta-Protein Precursor]
biology.protein
Phosphorylation
amyloid β
metabolism [Membrane Glycoproteins]
030217 neurology & neurosurgery
Function (biology)
metabolism [Alzheimer Disease]
Zdroj: Glia
Glia 69(12), 2917-2932 (2021). doi:10.1002/glia.24077
ISSN: 0894-1491
DOI: 10.1002/glia.24077
Popis: Funder: Canadian Institutes of Health Research; Id: http://dx.doi.org/10.13039/501100000024
Funder: Alzheimer's Association (Zenith Award)
Funder: UK Alzheimer Society and ARUK
Funder: Wellcome Trust Collaborative Award in Science
Rare coding variants of the microglial triggering receptor expressed on myeloid cells 2 (TREM2) confer an increased risk for Alzheimer's disease (AD) characterized by the progressive accumulation of aggregated forms of amyloid β peptides (Aβ). Aβ peptides are generated by proteolytic processing of the amyloid precursor protein (APP). Heterogeneity in proteolytic cleavages and additional post-translational modifications result in the production of several distinct Aβ variants that could differ in their aggregation behavior and toxic properties. Here, we sought to assess whether post-translational modifications of Aβ affect the interaction with TREM2. Biophysical and biochemical methods revealed that TREM2 preferentially interacts with oligomeric Aβ, and that phosphorylation of Aβ increases this interaction. Phosphorylation of Aβ also affected the TREM2 dependent interaction and phagocytosis by primary microglia and in APP transgenic mouse models. Thus, TREM2 function is important for sensing phosphorylated Aβ variants in distinct aggregation states and reduces the accumulation and deposition of these toxic Aβ species in preclinical models of Alzheimer's disease.
Databáze: OpenAIRE
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