Brain cells neuroprotection induced by TNF-α and LRP5

Area of Science:

• Cardiovascular Biology
• Neuroinflammation
• Molecular Signaling

Background:

• Acute myocardial infarction (AMI) induces systemic inflammation, potentially causing brain damage.
• The role of the Low-Density Lipoprotein Receptor-Related Protein 5 (LRP5)-mediated canonical WNT pathway in brain injury post-MI is not understood.

Purpose of the Study:

• To investigate the role of LRP5 in the brain's response to acute myocardial infarction (AMI).
• To elucidate the cell-specific mechanisms of LRP5 in neuroinflammation following cardiac injury.

Main Methods:

• Myocardial infarction (MI) was induced in wild-type (Wt) and Lrp5 knockout (Lrp5^-/-) mice.
• Infarct size, mortality, and serum effects on neuronal cultures were assessed.
• Tumor Necrosis Factor-alpha (TNF-α) effects were studied in LRP5-silenced neurons and microglia, analyzing apoptosis and signaling pathways (WNT/β-catenin, NF-κB).

Main Results:

• Lrp5^-/- mice exhibited increased mortality and larger infarcts; their serum promoted neuronal apoptosis.
• TNF-α provided neuroprotection independently of LRP5 and NF-κB in neurons.
• In microglia, TNF-α-induced survival and Bcl2 upregulation were dependent on both LRP5 and NF-κB signaling.

Conclusions:

• LRP5 deficiency exacerbates cardiac injury and increases neuronal vulnerability to inflammatory mediators.
• LRP5 mediates TNF-α-dependent microglial survival via NF-κB, while neuronal responses to TNF-α are LRP5-independent.
• These findings highlight cell-type-specific functions of LRP5 in the inflammatory response to MI, paving the way for further research.