Feinstein Institutes for Medical Research
Litwin-Zucker center for the study of Alzheimer's disease and memory disorders
Dr. Giliberto’s approach to Medicine, Neurology and Alzheimer’s disease (AD) has always been dual: basic research and clinical practice. He has worked and collaborated with great scientists, such as Massimo Tabaton, George Perry, Mark Smith, Pierluigi Gambetti, Antonio Uccelli, Luciano D’Adamio and Peter Davies. The work with Dr. D’Adamio at Albert Einstein College of Medicine, lead to identify APP processing modulators, including ITMB2 (BRI2). At the Feinstein Institutes, Dr. Giliberto collaborates with a diverse range of excellent scientists, expanding the focus of his research to tau, microglia and the immune response, cell cycle and the treatment of tau pathology with engineered antibodies. Dr. Giliberto works with patients affected by Alzheimer’s disease and other dementias, providing clinical care and trials, helping them and their families to cope with the disruption that this disease brings to their lives. This dual role has allowed him to broaden his view of the disease, as the inspiration he receives from patients at every encounter is invaluable. Dr. Giliberto teaches clinical neurology to medical students, Neurology, Medicine and Psychiatry residents at Hofstra University and North Shore University Hospital, and trains MD/PhD and PhD students in the laboratory at the Feinstein Institutes.

Presenter of 1 Presentation

INTERFERON REGULATORY FACTOR 5 (IRF5) MODULATES TAU ACCUMULATION IN ALZHEIMER’S DISEASE.

Session Type
SYMPOSIUM
Date
Fri, 18.03.2022
Session Time
02:45 PM - 04:45 PM
Room
ONSITE: 114
Lecture Time
04:00 PM - 04:15 PM

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.

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