Discoidin domain receptor inhibition reduces neuropathology and attenuates inflammation in neurodegeneration models

Michaeline Hebron; Margo Peyton; Xiaoguang Liu; Xiaokong Gao; Ruochong Wang; Irina Lonskaya; Charbel E-H Moussa

doi:10.1016/j.jneuroim.2017.07.009

Discoidin domain receptor inhibition reduces neuropathology and attenuates inflammation in neurodegeneration models

J Neuroimmunol. 2017 Oct 15;311:1-9. doi: 10.1016/j.jneuroim.2017.07.009. Epub 2017 Aug 12.

Authors

Michaeline Hebron¹, Margo Peyton¹, Xiaoguang Liu¹, Xiaokong Gao¹, Ruochong Wang¹, Irina Lonskaya¹, Charbel E-H Moussa²

Affiliations

¹ Department of Neurology, Laboratory for Dementia and Parkinsonism, Translational Neurotherapeutics Program, National Parkinson's Foundation Center of Excellence, Georgetown University Medical Center, 3970 Reservoir RD, NW. Washington D.C. 20007, USA.
² Department of Neurology, Laboratory for Dementia and Parkinsonism, Translational Neurotherapeutics Program, National Parkinson's Foundation Center of Excellence, Georgetown University Medical Center, 3970 Reservoir RD, NW. Washington D.C. 20007, USA. Electronic address: cem46@georgetown.edu.

PMID: 28863860
DOI: 10.1016/j.jneuroim.2017.07.009

Abstract

The role of cell surface tyrosine kinase collagen-activated receptors known as discoidin domain receptors (DDRs) is unknown in neurodegenerative diseases. We detect up-regulation in DDRs level in post-mortem Alzheimer and Parkinson brains. Lentiviral shRNA knockdown of DDR1 and DDR2 reduces the levels of α-synuclein, tau, and β-amyloid and prevents cell loss in vivo and in vitro. DDR1 and DDR2 knockdown alters brain immunity and significantly reduces the level of triggering receptor expressed on myeloid cells (TREM)-2 and microglia. These studies suggest that DDR1 and DDR2 inhibition is a potential target to clear neurotoxic proteins and reduce inflammation in neurodegeneration.

Keywords: Alzheimer; DDRs; Microglia; Parkinson; TREM2.

MeSH terms

Alzheimer Disease / complications*
Alzheimer Disease / pathology*
Alzheimer Disease / therapy
Amyloid beta-Peptides / metabolism
Amyloid beta-Protein Precursor / genetics
Amyloid beta-Protein Precursor / metabolism
Animals
Case-Control Studies
Cell Line, Tumor
Cytokines / metabolism
Discoidin Domain Receptors / antagonists & inhibitors
Discoidin Domain Receptors / genetics
Discoidin Domain Receptors / metabolism*
Encephalitis / drug therapy
Encephalitis / metabolism
Female
Hippocampus / metabolism
Humans
Male
Mice
Mice, Transgenic
Mutation / genetics
Neuroblastoma / pathology
Parkinson Disease / complications*
Parkinson Disease / pathology*
Parkinson Disease / therapy
Peptide Fragments / metabolism
Rats
Up-Regulation / physiology
alpha-Synuclein / genetics
alpha-Synuclein / metabolism

Substances

Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Cytokines
Peptide Fragments
alpha-Synuclein
amyloid beta-protein (1-42)
Discoidin Domain Receptors