Brain immune cell responses in Alzheimer’s disease

Overview: Deletion of the neurodegenerative disease-associated microglial gene CX3CR1 exacerbated the disease state and increased plaque accumulation in the brain of a mouse model of Alzheimer’s disease. Deficiency of this gene also impaired microglia migration into plaques.

sauce: Indiana University

Researchers at the Indiana University School of Medicine are investigating how genetic defects in immune cells shape the progression of Alzheimer’s disease.

Research published in molecular neurodegenerationfound that deletion of CX3CR1, a microglial gene associated with neurodegenerative disease, exacerbated pathology and plaque accumulation in the brain in an Alzheimer’s disease animal model. Deficiency of this gene also impaired the migration of brain immune cells, microglia, into plaques.

“This study shows that in the absence of CX3CR1, Alzheimer’s microglia become dysfunctional early in the disease course, and this dysfunction triggers a cascade of neurotoxic events in the brain,” says Shweta. Puntambekar, MS, Ph.D., Research Assistant Professor of Medicine and Molecular Genetics.

“For the larger research community, this work will help target this cell type early in the disease to modulate how the disease progresses in the brain and ultimately the cognitive outcome of Alzheimer’s disease.” It shows you exactly how to do it.”

Previous studies in both humans and animals have shown that CX3CR1 is downregulated in neurodegenerative diseases upon activation of microglia. A loss-of-function gene variant, CX3CR1-V249I, was first identified and associated with macular degeneration and later shown to be associated with neurodegeneration in Alzheimer’s disease and ALS.

Puntambekar, lead author of the journal article, said the study also investigated the relationship between amyloid beta and tau, a hallmark protein commonly associated with neurodegenerative diseases, in the brain. Amyloid-beta protein clumps together to form plaques and disrupt neuronal connections. Tau is then formed in the brain after amyloid plaques.

“This study not only makes connections between amyloid and tau, but how microglia can shape the entire disease process,” Puntambekar said.

Without this gene, microglia, which serve as the first line of defense against viruses, toxins and damaged neurons, cannot approach plaque and clear proteins. This occurs early in the disease and leads to more neurotoxic events, such as accumulation of other toxic species of amyloid-beta and exacerbation of tau in later disease stages.

Some of these species of amyloid-beta accumulate in the brain as soluble plaques, rather than depositing in the brain as ‘insoluble’ plaques, and have also been shown to be associated with cognitive decline. It increased in the absence of CX3CR1, she added.

Most treatments that target the amyloid-beta protein in the brain focus on insoluble plaque, but for years, drugs have proven ineffective in clinical trials.

“We will use this new data set to explore whether the limited clinical efficacy of Alzheimer’s disease treatments is due to failure to target the correct species of amyloid beta, and to explore other possibilities for better cognitive outcomes.” You can now ask if we should start targeting the soluble species of

About this Alzheimer’s Disease Research News

author: press office
sauce: Indiana University
contact; Press Office – Indiana University
image: image is public domain

See also

Original research: open access.
“CX3CR1 deficiency exacerbates amyloid-driven neuropathology and cognitive decline in Alzheimer’s diseaseShweta S. Puntambekar and others molecular neurodegeneration

Overview

CX3CR1 deficiency exacerbates amyloid-driven neuropathology and cognitive decline in Alzheimer’s disease

Background

Despite its identification as a key checkpoint regulator of microglial activation in Alzheimer’s disease, the overarching role of CX3CR1 signaling in the regulatory mechanisms of Aβ-driven neurodegeneration, including the accumulation of hyperphosphorylated tau, is poorly understood. Not.

methodology

Accumulation of soluble and insoluble Aβ species, microglial activation, synaptic dysregulation, and neurodegeneration are investigated in 5xFAD at 4 and 6 months of age.Cx3cr1^+/+ and 5xFAD;Cx3cr1^−/− Mice using immunohistochemistry, western blotting, transcriptome and quantitative real-time PCR analysis of purified microglia. flow cytometry-based, in vivo Aβ uptake assays are used to characterize the effects of CX3CR1 signaling on microglial phagocytosis and lysosomal acidification as an indicator of methoxy-X-04 clearance⁺ fibrillar Aβ. Finally, using the Y-maze test, Cx3cr1 Deficiency of working memory.

result

disease progression in 5xFAD;Cx3cr1^−/− Mice are characterized by increased deposition of filamentous plaques indicative of defects in microglial plaque engagement. Her Aβ phagocytosis and lysosomal acidification of microglia in 5xFAD.Cx3cr1^−/− mouse is broken in vivo. Interestingly, Cx3cr1 Deficiency results in increased accumulation of neurotoxic oligomeric Aβ, along with severe neuritogenic dystrophy, preferential loss of postsynaptic density, exacerbated tau pathology, neuronal loss and cognitive impairment. Combined transcriptome analysis using cortical RNA and qRT-PCR using purified microglia from 6-month-old mice showed her dysregulation of TGFβ signaling and increased ROS metabolism in 5xFAD. I was.Cx3cr1^−/− mouse. Finally, his 5xFAD microglia at 6 months of age.Cx3cr1^−/− Mice develop a ‘degenerate’ phenotype characterized by increased levels. CCl2, CCl5, IL-1β, Puten When Sibu with reduction TNF, IL-6 When Tgfβ1 mRNA.

Conclusion

Cx3cr1 Deficiency impairs microglial uptake and degradation of fibrillar Aβ, thereby causing increased accumulation of neurotoxic Aβ species. moreover, Cx3cr1 It causes microglial dysfunction represented by suppression of TGFβ signaling, increased oxidative stress response and dysregulation of proinflammatory activation.Our results suggest that Aβ-driven microglial dysfunction Cx3cr1^−/− Mice exacerbate tau hyperphosphorylation, neurodegeneration, synaptic dysregulation, and impair working memory.