CXCR4 involvement in neurodegenerative diseases

Abstract

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.

Microglial Activation and Inflammation as a Factor in the Pathogenesis of Progressive Supranuclear Palsy (PSP)

“…IL-2 and GSK3B are interpreted as regulators of T and natural killer cells, which were previously identified as playing a role in neurodegeneration in PD and AD ( Ishizawa and Dickson, 2001 ). The activation of microglia was verified in a study evaluating 10 patients with PSP and 5 patients with CBD via immunochemical post-mortem analysis ( Bonham et al, 2018 ). Differences were observed in the microglia of patients with these tauopathies and the controls.…”

CXCR4-directed theranostics in oncology and inflammation

“…Moreover, chronic inflammation, and thus local infiltration with CXCR4-expressing immune cells, strongly promotes carcinogenesis of esophageal cancer [ 14 ]. Aside from its involvement in various inflammation-related processes, CXCR4 dysregulation was also found to significantly contribute to neurodegenerative diseases [ 15 ].…”

One decade ago, one decade ahead in progressive supranuclear palsy

“…32 The CXCR4 SNP has also been identified as a shared contributor to the risk for PSP and PD. 33 The importance of GWASs lies in their ability to provide insight into disease mechanisms, and thus into treatment targets, without requiring any a priori hypothesis to guide discovery. 25,34 In the case of PSP, the haplotypes and SNPs associated with the MAPT locus alter the risk of developing PSP by influencing tau or tau isoform expression, which, in turn, can influence the propensity of tau to acquire pathological properties.…”

“…26 Finally, CXCR4 participates in microglial activation. 33 Microglial activation colocalizes and correlates with tau pathology in PSP, but its role is not well understood. 43,44 It has been suggested that microglia participates in the propagation of pathology.…”