TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss.

Details

Serval ID
serval:BIB_2305C5A91AA5
Type
Article: article from journal or magazin.
Collection
Publications
Title
TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss.
Journal
Neuron
Author(s)
Paolicelli R.C., Jawaid A., Henstridge C.M., Valeri A., Merlini M., Robinson J.L., Lee E.B., Rose J., Appel S., Lee V.M., Trojanowski J.Q., Spires-Jones T., Schulz P.E., Rajendran L.
ISSN
1097-4199 (Electronic)
ISSN-L
0896-6273
Publication state
Published
Issued date
19/07/2017
Peer-reviewed
Oui
Volume
95
Number
2
Pages
297-308.e6
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Microglia coordinate various functions in the central nervous system ranging from removing synaptic connections, to maintaining brain homeostasis by monitoring neuronal function, and clearing protein aggregates across the lifespan. Here we investigated whether increased microglial phagocytic activity that clears amyloid can also cause pathological synapse loss. We identified TDP-43, a DNA-RNA binding protein encoded by the Tardbp gene, as a strong regulator of microglial phagocytosis. Mice lacking TDP-43 in microglia exhibit reduced amyloid load in a model of Alzheimer's disease (AD) but at the same time display drastic synapse loss, even in the absence of amyloid. Clinical examination from TDP-43 pathology cases reveal a considerably reduced prevalence of AD and decreased amyloid pathology compared to age-matched healthy controls, confirming our experimental results. Overall, our data suggest that dysfunctional microglia might play a causative role in the pathogenesis of neurodegenerative disorders, critically modulating the early stages of cognitive decline.
Keywords
Amyloid/genetics, Amyloid/metabolism, Amyotrophic Lateral Sclerosis/pathology, Animals, Brain/metabolism, Brain/pathology, Cognition/physiology, DNA-Binding Proteins/genetics, Mice, Transgenic, Microglia/metabolism, Synapses/metabolism, Synapses/pathology, Alzheimer’s Disease, Amyloid, Amyotrophic Lateral Sclerosis, Clearance, Frontotemporal Lobar Degeneration, Microglia, Phagocytosis, Synapse Loss, Synaptic Pruning, TDP-43, Tardbp
Pubmed
Web of science
Open Access
Yes
Create date
18/12/2018 10:29
Last modification date
20/08/2019 13:00
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