Our original proposal represents a revolutionary new approach in understanding and treating Alzheimer’s disease (AD). It was based on a breakthrough discovery that we made prior to the submission, that the transient reduction of systemic immune suppression (by reducing FoxP3 regulatory T cells or by blocking the inhibitory Programmed-death (PD)-1/PD-L1 immune checkpoint pathway), is able to arrest local brain inflammation, to modify disease pathology, and reverse cognitive loss in mouse models of AD, and in aging. This approach is the first attempt at using immunotherapy to activate systemic immunity in the treatment of AD, and is opposite to the immunosuppressive approach, which was based on the belief prevailing for decades that brain inflammation should be directly suppressed. Overall, our new understanding suggests that by empowering the systemic immune system, numerous factors that go awry in the brain are addressed, including ones that that are yet to be characterized. Such an approach is different from the previous view of AD as a brain-autonomous disease, in which treatment attempts were directed towards a single specific risk factor within the AD brain, such as Aβ, tau, or acetylcholine, which - at best- showed limited efficacy, and failed to restore cognition or modify the disease. We believe that beyond its potential use in therapy, our paradigm offers an ideal platform to further probe AD pathophysiology, and to attain in-depth understanding of processes in the brain that are affected by the systemic immune system in health and disease. Accordingly, blocking systemic immune suppression will enable us to identify key events that should be boosted to protect the brain and prevent AD, or alternatively, those that should be arrested to restore lost function once disease occurs. It remains critical to fully characterize the nature and phenotype of the immune cells inside and outside the brain that participate in such healing processes, at all stages of the disease, as it is very likely that the needs of the brain change along the disease course.
During the 5 years since we received the present grant, we have accomplished all the set goals, including identification of pivotal mechanisms/pathways that can be restored or modified within the brain in order to arrest and even reverse cognitive decline in AD, and more critically, to identify key life-long mechanisms through which the immune system protects the mind and prevents onset of dementia. Addressing these questions using the multidisciplinary tools and expertise at our disposal will pave the way for developing a novel next-generation therapy, by either targeting additional and selective immune checkpoint pathways, or identifying a specific immune-based therapeutic target, for prevention and treatment of AD. Together, support from the ERC helped us reach our goal of establishing our pre-clinical approach to fight AD.
