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Age-Related Changes in Neuron-Microglia Interaction Mediated by Fractalkine Under Inflammatory Conditions
Rommy von Bernhardi1,2, Franchesca Cortes1, Claudia Narea1
1Faculty of Sciences, Universidad San Sebastian, Santiago 7510602, Chile.
Abstract:
Ageing results in an increased microglial activation and neuroinflammation. We are interested in assessing ageing-dependent changes in the amount and fractalkine (CX3CL1) proteoforms participating in neuron-microglia crosstalk that could be involved in microglia activation. We analysed age-dependent changes in CX3CL1, CX3CR1, and TGFβ mRNAs using RT-qPCR and CX3CL1 proteoforms using Western blot, in 3 to 20-month-old WT mice and an inflammatory mouse model (SRA-/-) treated with 0.5 mg/kg of intraperitoneal LPS, 2 ng of intrathecal TGFβ, or a vehicle. CX3CL1, CX3CR1, and TGFβ were affected by ageing. CX3CL1 mRNA was similar in young and adult mice but decreased by 52% in >20-month-old mice; adult mice showed a 3-fold increase in 70 kDa soluble CX3CL1. CX3CR1 showed a progressive increase, reaching a 2-fold increase in >20-month-old mice. TGFβ expression and cytokine reached their highest levels (3-fold increase) in adult mice and were reduced by 45% in >20-month-old mice. Inflammation, especially in SRA-/- mice, produced an increase in CX3CL1 mRNA in adult mice and a maximal CX3CR1 mRNA level in old mice, which were nearly abolished by TGFβ. Our findings show age-related changes in CX3CL1 and TGFβ, with the highest levels observed in adult mice, an age at which the early mechanisms leading to neurodegenerative disease initiate.
Insights
Ageing alters fractalkine (CX3CL1) and TGFβ levels, impacting neuron-microglia communication. These changes, particularly elevated in adult mice, may initiate early neurodegenerative processes.
Area of Science:
- Neuroscience
- Immunology
- Aging Research
Background:
- Aging is associated with increased microglial activation and neuroinflammation.
- Neuron-microglia crosstalk, mediated by fractalkine (CX3CL1) and its receptor CX3CR1, plays a crucial role in regulating microglial function.
- Dysregulation of this pathway may contribute to age-related neurological decline.
Purpose of the Study:
- To investigate age-dependent changes in CX3CL1 and CX3CR1 expression and CX3CL1 proteoforms.
- To assess the impact of inflammation on these age-related alterations.
- To understand the role of TGFβ in modulating these pathways during aging and inflammation.
Main Methods:
- Analysis of CX3CL1, CX3CR1, and TGFβ mRNA levels using RT-qPCR in mice of different ages (3 to >20 months).
- Quantification of CX3CL1 proteoforms via Western blot.
- Utilized wild-type (WT) mice and an inflammatory model (SRA-/-) subjected to LPS or TGFβ treatment.
Main Results:
- CX3CL1 mRNA decreased in aged mice (>20 months), while soluble CX3CL1 increased in adult mice.
- CX3CR1 mRNA showed a progressive increase with age, peaking in aged mice.
- TGFβ levels were highest in adult mice and decreased in aged mice; inflammation exacerbated CX3CL1 and CX3CR1 mRNA, effects partially mitigated by TGFβ.
Conclusions:
- Aging significantly alters CX3CL1 and TGFβ expression, with peak levels observed in adult mice.
- These age-related changes in neuron-microglia signaling molecules may represent early events initiating neurodegenerative disease.
- Inflammation further modulates these pathways, highlighting their complex role in aging and brain health.
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