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

•DDR knockdown reduces the levels of neurotoxic proteins and prevents cell loss.•DDR knockdown alters brain immunity and significantly.•DDR knockdown reduces the level of TREM-2 and microglia in PD models.•DDR inhibition is a novel target in neurodegeneration.

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.

Graphical abstractIn neurodegeneration, Discoidin domain receptors (DDRs) are upregulated in association with accumulation of neurotoxic proteins, increased inflammation and microglial activity. Lentiviral shRNA knockdown of DDRs reduces neurotoxic protein levels and regulates brain immunity via possible alteration of TREM2 + microglial function, leading to neuroprotection.Download high-res image (165KB)Download full-size image