by Indiana University School of Medicine
Accelerated plaque deposition in 5xFAD mice deficient in Cx3cr1. (A) Accumulation of MOAB2+ Aβ42 plaques in (top panels) 4 month-old vs. (bottom panels) 6 month-old 5xFAD;Cx3cr1+/+ and 5xFAD; Cx3cr1−/− mice. Scale bars = 500 μm. Quantification of %MOAB2+ areas in the (B) cortex and (C) hippocampus of 4 and 6 month-old 5xFAD;Cx3cr1+/+ (black bars) and 5xFAD;Cx3cr1−/− (gray bars) mice. Data in B,C represent mean proportions of cortical and hippocampal MOAB2+ areas quantified using n = 6 animals (3 females, 3 males) per genotype, per time-point. Error bars represent SEM. Statistical analysis done using two-way ANOVA (pint cortex < 0.0001, pint hippocampus < 0.0001) followed by Tukey’s post hoc tests. (D) ThioS+ plaques visualized in the (top panels) cortex and (bottom panels) hippocampus of 6 month-old 5xFAD mice with and without Cx3cr1. Scale bars = 50 µm. (E) Identification of morphologically distinct ThioS+ plaques based on circularity scores as follows – Diffuse: Circularity = 0.00–0.14, Intermediate: Circularity = 0.15–0.28, Compact: Circularity = > 0.30. Scale bars = 30 µm. Proportion of ThioS+ plaques with diffuse (orange), intermediate (gray) and compact (green) circularities were quantified in the (F) cortex (G) hippocampus of 6 month-old 5xFAD;Cx3cr1+/+ and 5xFAD;Cx3cr1−/− mice. Data in F,G represent mean proportions of each plaque type quantified using 6 mice (3 females, 3 males) per genotype at each age. Circularity analysis was based on 250–300 cortical plaques and 100–150 hippocampal plaques per animal, per genotype at each age. Error bars represent SEM. Statistical analysis done using two-way ANOVA (pint cortex and pint hippocampus = 0.0002) followed by Tukey’s post hoc tests. (H) Quantification of cortical area occupied by OC+ oAβ in 4- and 6-month-old 5xFAD;Cx3cr1+/+ (black bars) and 5xFAD;Cx3cr1−/− (gray bars) mice. Data represents mean proportion of OC+ cortical area quantified using n = 6 (3 females, 3 males) of each genotype at each age. Statistical analysis done using two-way ANOVA (pint = 0.03) followed by Tukey’s post hoc tests. (I) Accumulation of soluble OC+ oAβ around ThioS+ plaques in 6 month-old 5xFAD;Cx3cr1+/+ and 5xFAD;Cx3cr1.−/− mice. Scale bars = 100 μm. *p < 0.01, **p < 0.001, ***p < 0.0001. ****p < 0.00001. All histology data representative of n = 6 mice (3 females, 3males) per genotype at each age analyzed. Credit: Molecular Neurodegeneration (2022). DOI: 10.1186/s13024-022-00545-9
Indiana University School of Medicine researchers are investigating how the deficiency of a gene in immune cells can shape the progression of Alzheimer’s disease.
The study, published in Molecular Neurodegeneration, found that deleting CX3CR1, a microglial gene associated with neurodegenerative diseases, in Alzheimer’s disease animal models resulted in an aggravated disease state and accumulation of plaques in the brain. The deficiency of the gene also impaired the movement of microglia—the brain’s immune cells—toward the plaques.
“This investigation shows that microglia in Alzheimer’s disease become dysfunctional earlier in the disease course in the absence of CX3CR1, and this dysfunction results in the cascade of neurotoxic events in the brain,” said Shweta Puntambekar, MS, Ph.D., assistant research professor of medical and molecular genetics.
“For the larger research community, this research pinpoints how we can target this cell type early in the disease in order to modulate how the disease progresses in the brain and ultimately modulate cognitive outcomes in Alzheimer’s disease.”
CX3CR1 has been shown in both past human and animal studies to be downregulated in neurodegenerative diseases when microglia are activated. The CX3CR1-V249I, a loss-of-function gene variant, was first identified and associated with macular degeneration and was later shown to relate to neurodegeneration in Alzheimer’s disease and ALS.
Puntambekar, first author of the journal article, said the study also looked at the connection between amyloid beta and tau in the brain—hallmark proteins commonly associated with neurodegenerative diseases. Amyloid beta proteins clump together and form plaques, which destroy nerve cell connections. Tau then can later form in the brain after amyloid plaques.
“The study has made a connection not just between amyloid and tau, but how microglia can shape the entire disease process,” Puntambekar said.
In the absence of this gene, the microglia—which act as the first line of defense against viruses, toxic materials and damaged neurons—cannot move closer to plaques to clear up proteins. This occurs early in the disease and leads to more neurotoxic events, such as accumulations of other toxic species of amyloid beta and aggravated tau in later disease stages.
Some of those species of amyloid beta aren’t deposited in the brain as “insoluble” plaques, Puntambekar said, but rather accumulate in the brain as soluble plaques and have been shown to also be associated with cognitive decline. These species were increased in the absence of CX3CR1, she added.
Most therapies that target amyloid beta proteins in the brain focus on insoluble plaques, but drugs for years have been proven ineffective in clinical trials.
“With this new data set, we can now start asking if the limited clinical efficiencies of Alzheimer’s disease therapies are due to not targeting the correct species of amyloid beta and whether we should start targeting other soluble species to get better cognitive outcomes,” Puntambekar said.
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