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Immune checkpoint blockade for fighting Alzheimer’s disease

Periodic Reporting for period 4 - ImmuneCheckpointsAD (Immune checkpoint blockade for fighting Alzheimer’s disease)

Reporting period: 2021-12-01 to 2022-11-30

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.
Our overall goal in the present proposal has been to exploit our novel experimental paradigm of modifying AD pathophysiology by empowering the immune system, without targeting a specific disease-escalating factor in the brain. We anticipated that our studies would lead to a new understanding of how the immune system provides life-long support for brain function, and how targeting only the systemic immune system can drive a cascade of events that comprehensively modify AD pathology. Accordingly, we discovered key, previously intractable, molecular and cellular processes that should be restored in the brain to modify or prevent AD progression; we expect that our results will explain why previous treatments that were thought to address the hallmarks of the disease were not sufficient.

During the research period supported by the ERC the following was achieved:
1. We established that immunotherapy, using the approach of immune checkpoint blockade, affects multiple parameters that contribute disease escalation in Alzheimer’s disease, including reducing local brain inflammation, reducing accumulation of toxic proteins, reducing synapse and neuronal loss, and arresting cognitive loss.
2. We demonstrated that our immunotherapy is effective independently of the primary cause of the disease, as it was found to be effective in animal models of AD and tauopathy.
3. The antibody used for immunotherapy, i.e. anti-PD-L1, is not needed in the brain; rather, it serves as a vehicle to facilitate homing of immune cells to the central nervous system. This understanding allowed us to optimize translation of the therapy when going forward to the clinic.
4. Our understanding of the fate of microglia in AD allowed us to establish that microglia are not sufficient in fighting disease, and that bone-marrow derived macrophages are the key players. Through this understanding we were able to demonstrate that our proposed therapy bypasses microglial insufficiency and cell polymorphism.
5. Our studies contributed to optimization of the immunotherapy to treat AD.
6. Understanding that AD is not solely a disease of the brain.
Our success exceeded expectations. Our results:
1. Provide preclinical support for the kickoff of the first-in-human trial in AD, using our immunotherapy approach.
2. Establish immunotherapy as a novel approach to treat neurodegenerative disease.
3. Further support the key role of brain-immune relationships in life-long brain maintenance and repair, and identify aging of the immune system as a key player in AD.
4. Further establish the importance of the field, which was initiated by my team in 1998, as summarized by a Nature journalist in June 2022 ("The immune cells are guardians of the brain", (https://www.ncbi.nlm.nih.gov/pubmed/35650361(opens in new window)) and in the special issue of Neuron, in which I proposed viewing brain-immunity as an ecosystem ( https://www.ncbi.nlm.nih.gov/pubmed/36150394(opens in new window)).
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