Presenter of 1 Presentation
INTERFERON REGULATORY FACTOR 5 (IRF5) MODULATES TAU ACCUMULATION IN ALZHEIMER’S DISEASE.
Abstract
Aims
The innate immune system reacts to tau accumulation to limit its spread. However, dysfunctional microglia activation may cause hyper-inflammation and worsened pathology. We identified the transcription factor interferon regulatory factor 5 (IRF5) as a new mediator of microglia activation in response to pathological tau and sought to define its role.
Methods
We analyzed human AD brains for IRF5 expression by Western blot and immunohistochemistry. In ageing wild-type and Irf5-/- mice intracranially injected with PHF-tau, we measured tau levels and characterized microglia numbers and function. In vitro, we assessed the response to PHF-Tau using imaging flow cytometry on AMNIS Imagestream. Last, we tested the feasibility of in-vivo IRF5 inhibition with a novel peptide inhibitor developed in our lab.
Results
We determined that: 1) IRF5 is overexpressed in AD brains and localizes in microglia, near plaque-like structures; 2) ageing Irf5-/- mice have higher levels of soluble tau; 3) after hippocampal injection of PHF tau, young Irf5-/- mice accumulate more soluble total tau in all brain regions than wild-type littermates; 4) PHF tau induces IRF5 nuclear translocation (i.e. activation) in cultured macrophages; 5) a novel IRF5 peptide inhibitor, N5-1, penetrated into the brain when injected IV, hence is a viable tool to modulate IRF5 function in vivo.
Conclusions
IRF5 is a regulator of microglia response to tau pathology. Modulation of IRF5 may be a key factor to maintain innate immune response to tau without causing hyper-inflammation.