Periodic Reporting for period 4 - ImmuneCheckpointsAD (Immune checkpoint blockade for fighting Alzheimer’s disease)
Reporting period: 2021-12-01 to 2022-11-30
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.
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.
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)).