Format

Send to

Choose Destination
Neuron. 2017 Jul 19;95(2):297-308.e6. doi: 10.1016/j.neuron.2017.05.037. Epub 2017 Jun 29.

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

Author information

1
Systems and Cell Biology of Neurodegeneration, IREM, University of Zurich, Schlieren, Switzerland. Electronic address: rosachiara.paolicelli@irem.uzh.ch.
2
Brain Research Institute, University of Zurich/ETH, Zurich, Switzerland.
3
Center for Cognitive and Neural Systems, University of Edinburgh, Edinburgh, UK.
4
Systems and Cell Biology of Neurodegeneration, IREM, University of Zurich, Schlieren, Switzerland.
5
Center for Molecular Cardiology - Vascular Aging & Stroke, University of Zurich, Schlieren, Switzerland.
6
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
7
Academic Neuropathology, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
8
ALS/MDA Center, The Methodist Hospital, Houston, TX, USA.
9
Department of Neurology, University of Texas, Health Science Center, Houston, TX, USA.
10
Systems and Cell Biology of Neurodegeneration, IREM, University of Zurich, Schlieren, Switzerland. Electronic address: lawrence.rajendran@irem.uzh.ch.

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:

Alzheimer’s Disease; Amyloid; Amyotrophic Lateral Sclerosis; Clearance; Frontotemporal Lobar Degeneration; Microglia; Phagocytosis; Synapse Loss; Synaptic Pruning; TDP-43; Tardbp

PMID:
28669544
PMCID:
PMC5519492
DOI:
10.1016/j.neuron.2017.05.037
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center