BRFAA - Biomedical Research Foundation Academy Of Athens
Biomedical Research Foundation Academy Of AthensAcademy Of Athens


Current evidence has suggested a crosstalk between the periphery and the brain during inflammation that affects neurodegenerative diseases. The interaction of the peripheral immune system and the nervous system is still not understood. The role of this interaction in the pathogenesis of neurodegenerative diseases as Alzheimer’s Disease (AD) is still unknown. The Georgopoulos’ lab focuses on this question conducting studies of neuro-immune interactions in preclinical AD mouse models to elucidate the role of peripheral immunity in AD.

Our studies have contributed to elucidating the significant role of peripheral immunity in regulating the immune-glial response in the brain and modifying amyloid deposition. We are interested in elucidating the role of immune molecules as TNF-a or regulators of the adaptive immunity as Ikaros. Our aim is to identify possible common disease pathways between peripheral immune-related pathologies such as rheumatoid arthritis or leukemia and neurogenerative diseases such as AD.

As cholesterol transport proteins, like ApoE, are major risk factors in AD, we are also interested in evaluating the contribution in AD pathogenesis of the cholesterol transport pathway, focusing on SR-BI, the HDL-cholesterol receptor, evaluating its role on the neuro-immune component of the disease.

Peripheral TNF-a as a modulator of brain immune response. We have previously shown that TNF-a affects amyloid plaque load, glial activation, and synaptic integrity in the brain of AD mice. This effect is associated with peripheral TNF-a and myeloid derived peripheral cells that infiltrate the brain and can be reversed by blocking TNF-a in the periphery. This is a finding with major therapeutic implications in AD. To further understand the molecular pathway involved we have focused on the role of TNFReceptor II and membrane TNF-a as anti-TNF-a therapies have been reported to have a positive effect on AD patients.

Ikaros as a regulator of amyloid deposition in the brain. Recent studies have implicated adaptive immunity in AD pathogenesis. We have found that deletion of Ikaros, a major regulator of the lymphoid lineage, involved in leukemia pathogenesis, can drastically restrict amyloid deposition in the AD mouse brain. We have found that Ikaros expressing peripheral immune cells can infiltrate amyloid deposits and modulate the IFN-γ pathway that has been recently involved in AD pathogenesis. Our findings support a mechanism in which γ-secretase is regulated by inflammation and can possibly have implications for AD therapy.

The role of peripheral SR-BI in amyloid deposition. We have shown that SR-BI regulates perivascular macrophages and modifies AD pathology in a mouse model. SR-BI is up-regulated in the brains of the AD mice and AD patients. To further elucidate the role of peripheral versus brain SR-BI we have generated a liver-expressing SR-BI mouse that lacks endogenous SR-BI and develops AD. Peripheral expression of SR-BI from the liver restores the cholesterol and fertility defects of the mice but does not restore SR-BI in the brain. In parallel we have generated a brain specific (astrocyte) expressing SR-BI mouse that develops AD. These transgenic mice backcrossed to the 5XFAD AD mouse model we help us to further elucidate the role of SR-BI in AD pathogenesis.