The study identified a subtype of microglia called CD83(+), associated with Alzheimer's disease (AD), present in greater numbers in the brains of individuals with the disease. These cells are linked to an increase in immunoglobulin G4 (IgG4) and the presence of human cytomegalovirus (HCMV) in various parts of the body, suggesting an interaction between the viral infection, the immune system and the progression of AD.
Recently, advances in single-nucleotide RNA sequencing (snRNAseq) technology have enabled a more detailed analysis of how brain cells function and behave in conditions such as Alzheimer's disease (AD).
This technique allows the study of gene expression at the cellular level, something that cannot be done with traditional tissue analysis methods.
A study based on data collected from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) brain donation program analyzed 481,840 nuclei from the superior frontal gyrus (a region of the brain) of 101 elderly individuals, including 66 with AD and 35 healthy controls.
The researchers identified a specific subtype of immune cells in the brain, called CD83(+) microglia, that were present in 47% of AD cases and 25% of healthy controls.
Microglia are immune cells in the brain that play essential roles in clearing cellular debris and responding to inflammation.
CD83(+) microglia are named because they express a marker called CD83, but they also have other associated genes. Among AD cases, these microglia have not been associated with common risk factors, such as the presence of the APOE4 genetic variant, age, or other comorbidities.
However, their presence has been associated with an increase in the burden of neuritic plaques (abnormal protein deposits in the brain) and neurofibrillary tangles (a hallmark of AD).
Further analysis has shown that these microglia are associated with alterations in critical biological pathways, such as cellular senescence, iron and lipid processing, and complement activation.
These functions are important for brain development and health. One intriguing factor identified was the noncoding RNA AC131944.1. Unlike protein-coding RNA, this type of RNA has regulatory functions, such as controlling the expression of other genes.
In the case of AC131944.1, it may be influencing genes linked to the critical functions mentioned above, playing a central role in the abnormal behavior of these microglia. This makes it a potential target for future studies and, possibly, for therapeutic interventions.
Since CD83 is also a marker of dendritic cells (which fight infections), researchers from Arizona State University, USA, hypothesized that the presence of CD83(+) microglia could be related to microbial or immunological alterations.
Data collected from transverse colon (TC) samples from these individuals revealed elevated levels of a protein associated with IgG4 antibodies. This suggests that the immune system may be reacting to microbial stimuli in the gut differently in individuals with AD.
The idea that microbes may influence the risk or progression of AD is not new. Researchers have proposed this possibility since the early 20th century. However, no single pathogen has been consistently linked to AD.
In this study, scientists identified a significant association between the presence of human cytomegalovirus (HCMV), CD83(+) microglia, and IgG4 in various parts of the body, including the brain.
To better understand the link between HCMV and AD, the researchers used brain organoids (laboratory models of mini-brains). When infected with HCMV, these organoids began to exhibit typical signs of AD, such as the accumulation of Aβ42 and pTau-212 proteins and neuronal death.
This suggests that the virus may play a direct role in inducing AD features. Furthermore, the analysis showed that the presence of CD83(+) microglia and IgG4 may indicate an attempt by the immune system to tolerate HCMV infection.
This moderate immune response may protect against more aggressive cell destruction, but it may also allow the disease to progress.
HCMV infection of human brain organoids accelerates the neuropathological hallmarks of AD. (A) HCMV infection of human brain organoids demonstrates significant correlations between Aβ42 and pTau-212, and HCMV abundance in (B–C) live and (D–E) dead cells. Representative photomicrographs shown. Aβ42, amyloid beta-42; AD, Alzheimer’s disease; CSF, cerebrospinal fluid; HCMV, human cytomegalovirus.
The study identified significant associations between CD83(+) microglia, HCMV, and IgG4 in multiple sites of the body and central nervous system. The findings point to complex interactions between microbes, the immune system, and AD progression.
The presence of HCMV in the nervous system and other tissues opens the possibility of targeted antiviral interventions. However, the exact mechanisms still need to be further explored, including factors that lead some people exposed to HCMV to develop AD while others do not.
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Alzheimer's disease-associated CD83(+) microglia are linked with increased immunoglobulin G4 and human cytomegalovirus in the gut, vagal nerve, and brain
Benjamin P. Readhead and Diego F. Mastroeni et al.
Alzheimer’s & Dementia. 19 December 2024
Abstract:
While there may be microbial contributions to Alzheimer's disease (AD), findings have been inconclusive. We recently reported an AD-associated CD83(+) microglia subtype associated with increased immunoglobulin G4 (IgG4) in the transverse colon (TC). We used immunohistochemistry (IHC), IgG4 repertoire profiling, and brain organoid experiments to explore this association. CD83(+) microglia in the superior frontal gyrus (SFG) are associated with elevated IgG4 and human cytomegalovirus (HCMV) in the TC, anti-HCMV IgG4 in cerebrospinal fluid, and both HCMV and IgG4 in the SFG and vagal nerve. This association was replicated in an independent AD cohort. HCMV-infected cerebral organoids showed accelerated AD pathophysiological features (Aβ42 and pTau-212) and neuronal death. Findings indicate complex, cross-tissue interactions between HCMV and the adaptive immune response associated with CD83(+) microglia in persons with AD. This may indicate an opportunity for antiviral therapy in persons with AD and biomarker evidence of HCMV, IgG4, or CD83(+) microglia.
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