CXCR4 as an Indicator of Microglial Involvement in Neurodegenerative Diseases

The open access paper noted here reports on the use of a genetic analysis to shed further light on the relative importance of shared mechanisms across a range of neurodegenerative conditions in which tau aggregation is thought to be important. The researchers find associations in gene expression between these conditions that suggesting microglial dysfunction is an important common determinant of disease progression.

If one looks over all of the most common neurodegenerative diseases, patients exhibit a number of overlapping mechanisms that appear plausible as proximate causes of brain cell dysfunction and death. Some conditions share the aggregation of damaged proteins such as amyloid-β and tau. Most share harmful alterations in the behavior of immune cells such as microglia, either causing or responding to a state of raised chronic inflammation. The progression of vascular aging, leading to inadequate delivery of oxygen and nutrients, and mitochondrial dysfunction are also common in neurodegenerative conditions. All of these observations, sadly, tell us far less than we'd like about cause and effect in the aging brain. All of the signs progress over time, and absent technologies that can carefully block one of those signs, in order to see what happens next, it is very challenging to determine causality by observation alone.

Uncovering the shared genetic architecture across neurodegenerative diseases may elucidate underlying common disease mechanisms and promote early disease detection and intervention strategies. Progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson's disease (PD), and Alzheimer's disease (AD) are age-associated neurodegenerative disorders placing a large emotional and financial impact on patients and society. Despite variable clinical presentation, PSP, AD, and FTD are characterized by abnormal deposition of tau protein in neurons and/or glia. While PD is classically characterized by alpha-synuclein deposits, recent studies support the role of tau and neurofibrillary tangles in modifying PD clinical symptoms and disease risk.

Genome-wide association studies (GWAS) and candidate gene studies have identified single nucleotide polymorphisms (SNPs) in MAPT (which encodes tau) that increase risk for PSP, FTD, AD, and PD. However, beyond MAPT, the extent of genetic overlap across these diseases and its relationship with common pathogenic processes observed in PSP, FTD, AD, and PD remain poorly understood. Here, using previously validated methods, we assessed shared genetic risk across PSP, PD, FTD, and AD. We then applied molecular and bioinformatic tools to elucidate the role of these shared risk genes in neurodegenerative diseases.

We identified CXCR4 as a novel locus associated with increased risk for both PSP and PD. We found that CXCR4 and functionally associated genes exhibit altered expression across a number of neurodegenerative diseases. In a mouse model of tauopathy, CXCR4 and functionally associated genes were altered in the presence of tau pathology. Together, our findings suggest that alterations in expression of CXCR4 and associated microglial genes may contribute to age-associated neurodegeneration. Despite the lack of strong genetic association across these three neurodegenerative diseases, we found that CXCR4 expression was altered in brains that are pathologically confirmed for PSP, PD, and FTD. Thus, these findings support our hypothesis that these three neurodegenerative disorders share common pathobiological pathways.

CXCR4 is a chemokine receptor protein with broad regulatory functions in the immune system and neurodevelopment. CXCR4 has been shown to regulate neuronal guidance and apoptosis through astroglial signaling and microglial activation. Furthermore, it has been shown that CXCR4 is involved in cell cycle regulation through p53 and Rb. Our results provide additional evidence that immune and microglial dysfunction contribute to the pathophysiology in PSP, PD, and FTD. These findings have important implications for future work focused on monitoring microglial activation as a marker of disease progression and on developing anti-inflammatory therapies to modify disease outcomes in patients with neurodegenerative diseases.



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