Loss of Function of TREM2 Results in Cytoskeletal Malfunction in Microglia
Journal: Journal of Neurology and Neurobiology (Vol.4, No. 3)Publication Date: 2018-12-04
Authors : Alexandra E M Phillips Claudio Villegas-Llerena Thomas M Piers Katharina Cosker John Hardy Jennifer M Pocock;
Page : 1-11
Keywords : Microglia; Nasu-Hakola disease; Dementia; TREM2;
Abstract
Recent genome wide association studies (GWAS) have highlighted mutations in the gene Triggering receptor expressed on myeloid cells 2 (TREM2) as risk factors for the development of late onset Alzheimer's disease. In light of this, we generated heterozygous and homozygous knock-out clones in the BV2 rodent microglial cell line using CRISPR/cas9 genome editing technology. The heterozygous and homozygous clones were characterised as displaying less mRNA for TREM2 by qPCR, less cellular expression of TREM2 by Western blot and less shedding of soluble TREM2 by ELISA and a reduced cellular expression by immunolocalisation. In addition the heterozygous and homozygous BV2 cells showed a markedly different morphology to the wild-type cells and further analyses following phalloidin staining revealed changes in filopodial length as well as defects in membrane ruffling following stimulation with ATP or MCSF. In addition, expression of both mRNA by qPCR and protein by Western blot for ionized calcium-binding adapter molecule (Iba1) was significantly reduced in heterozygous and homozygous clones compared with wild type cells. Furthermore phagocytosis of pH rodo Escherichia coli particles by FACS analysis was significantly reduced in the homozygous clones. Taken together these data provide evidence of how TREM2 mutations may manifest to promote dysfunctional microglia in heterozygous disease (such as occurs in late-onset Alzheimer's disease) and homozygous disease (such as Nasu-Hakola disease), both of which lead to dementia.
Other Latest Articles
- White Shark Protein Metabolism may be a Model to Improve the Outcome of Cytotoxic Brain Tissue Edema and Cognitive Deficiency after Traumatic Brain Injury and Stroke
- A STATISTICAL APPROACH TOWARDS IMPROVING VIRTUAL INTERNSHIP EXPERIENCE
- DEXMEDETOMIDINE IN PARAVERTEBRAL BLOCK FOR BREAST CANCER SURGERIES- A WAY TOWARDS OPIOID FREE ANAESTHESIA
- Transformation of Radiologically Isolated Syndrome into Tumefactive Multiple Sclerosis
- Changes in Quality of Life in Children after Surgical Treatment of Drug-Resistant Temporal Lobe Epilepsy
Last modified: 2021-02-24 20:48:18