CXCR4 involvement in neurodegenerative diseases

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Bonham, LW 
Karch, CM 
Fan, CC 
Tan, C 
Geier, EG 

Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson's disease (PD) and Alzheimer's disease (AD). In addition to the MAPT H1 haplotype, we identified a variant near the chemokine receptor CXCR4 that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between CXCR4 and four microglia related genes, namely CXCL12, TLR2, RALB, and CCR5. Evaluating gene expression from post-mortem brain tissue, we found that expression of CXCR4 and microglial genes functionally related to CXCR4 was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of CXCR4 and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond MAPT, we show dysregulation of CXCR4 expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a 'network' of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases.

Animals, Brain, Gene Expression, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mice, Transgenic, Microglia, Neurodegenerative Diseases, Polymorphism, Single Nucleotide, Receptors, CXCR4, Risk Factors
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Translational Psychiatry
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Springer Nature
CurePSP (GRANT#489-10)
Isaac Newton Trust (1026(1))
Medical Research Council (G0301152)
Wellcome Trust (103838/Z/14/Z)
Medical Research Council (MC_U105597119)
Medical Research Council (MC_UU_00005/12)
We thank the International FTD-GWAS Consortium (IFGC), International Parkinson’s Disease Genomic Consortium (IPDGC) and International Genomics of Alzheimer’s Project (IGAP) for providing summary statistics data for these analyses. Further acknowledgments for IFGC, IPDGC and IGAP are found in the Supplemental material. This research was supported by grants from the National Institutes of Health (NIH-AG046374 [CMK] and K01 AG049152 [JSY]), Larry J. Hillblom Foundation (2016-A-005-SUP [JSY]), Research Council of Norway (#213837, #225989, #223273, and #237250/EU JPND [OAA]), South East Norway Health Authority (2013-123), Norwegian Health Association, the Radiological Society of North America (RMS1741 [LWB]) (RSD), ASNR Foundation AD Imaging Award (RSD), National Alzheimer’s Coordinating Center (NACC) Junior Investigator (JI) Award (RSD), the Tau Consortium (JSY), and Alzheimer's Society grant 284 (RF).