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Immune checkpoint blockade for fighting Alzheimer’s disease

Periodic Reporting for period 3 - ImmuneCheckpointsAD (Immune checkpoint blockade for fighting Alzheimer’s disease)

Reporting period: 2020-06-01 to 2021-11-30

Currently, there is no available treatment to modify Alzheimer's disease (AD). Therefore, understanding, and ultimately treating AD is a major need worldwide. Several pioneering discoveries were made by my team, attributing a key role to systemic immunity in brain maintenance and repair, and identifying unique interface within the brain’s borders through which the immune system assists the brain. These findings led us to suggest harnessing the immune system to fight AD and dementia, using immune checkpoint blockade (1-3). This discovery is revolutionary, as this disease was previously considered brain-centric. In our proposal, we suggested adopting our new experimental paradigm to discover mechanisms whereby the immune system supports the brain, identifying key/novel molecular and cellular processes at various stages of the disease that are responsible for cognitive decline long before neurons are lost, and whose reversal or modification is needed to mitigate AD pathology, and prevent cognitive loss. So far, our studies have successfully addressed these targets, and therefore, we believe that we will reach the ultimate goal of converting escalating untreatable AD into a chronic treatable condition.
References
1. Baruch K, Deczkowska A, David E, Castellano JM, Miller O, Kertser A, Berkutzki T, Barnett-Itzhaki Z, Bezalel D, Wyss-Coray T, Amit I, Schwartz M. 2014. Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science 346: 89-93
2. Baruch K, Deczkowska A, Rosenzweig N, Tsitsou-Kampeli A, Sharif AM, Matcovitch-Natan O, Kertser A, David E, Amit I, Schwartz M. 2016. PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease. Nat Med 22: 135-7
3. Baruch K, Rosenzweig N, Kertser A, Deczkowska A, Sharif AM, Spinrad A, Tsitsou-Kampeli A, Sarel A, Cahalon L, Schwartz M. 2015. Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer's disease pathology. Nat Commun 6: 7967
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 period that elapsed since the grant was initiated, we have accomplished the following:
Brief summary of results, based on the primary objectives listed in our proposal:


A1. Compare the potential of anti-PD-L1 and anti-PD-1 antibody blockade in the 5XFAD mouse model of Alzheimer’s disease

We showed that targeting PD-L1 is as effective as anti-PD-1 in enhancing cognitive performance and modifying disease pathology(1).
A2. Determine the relevance of blocking PD-/PD-L1 in several AD mouse models and conditions

We demonstrated that the efficacy of the treatment is not restricted to an animal model of amyloidosis, but that treatment is also effective in an animal model of Tauopathy (1). These results suggest that checkpoint blockade activates a common pathway of repair, irrespective of the primary cause of the disease.
B1. Characterize the dynamics of immune cells within the brain at the immunological and genomic levels
We performed flow cytometry and single cell RNA seq analyses of the myeloid cells within the brain, and showed that microglia and infiltrating macrophages display distinct profiles and different activities (1).
B2. Determine the function of the identified subset of microglia and the infiltrating immune cells in disease prevention and in repair
Using bone marrow-chimeric mice, we demonstrated that the molecules expressed by the infiltrating cells are pivotal for the effect on disease pathology and behavior; one such molecule is the MSR-1 (macrophage-scavenger receptor-1) (1). We have results from a study that is near completion showing that blocking entry of monocyte-derived macrophages abrogates the beneficial effect of anti-PD-L1 (2). Likewise, blocking the IFN-γ Receptor expressed by the choroid plexus reduced the beneficial effect of treatment, showing that the CP plays a key role in the beneficial effect of PD-L1 in AD (3).
We have analyzed additional brain populations using genomic tools, and found a novel subset of astrocytes that appears with the disease, with signature that partially overlaps with the unique subset of microglia in the disease (4). We are currently testing how this subset is influenced by the treatment.
C1. Determine the effect of PD-1/PD-L1 blockade on the dynamics of the systemic immune response
Using CytOF, we were able to show that PD-L1 blockade boosts the level of CCR2+ monocytes in the blood (2).
References
1. Rosenzweig N, Dvir-Szternfeld R, Tsitsou-Kampeli A, Keren-Shaul H, Ben-Yehuda H, Weill-Raynal P, Cahalon L, Kertser A, Baruch K, Amit I, Weiner A, Schwartz M. 2019. PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model. Nat Commun 10: 465
2. Ben-Yehuda H, Arad M, Peralta Ramos JM, Castellani G, Ferrera S, Schwartz M. 2020. PD-L1 blockade immunotherapy for treatment of tauopathies is CCL2 dependent. in preparation
3. Arad M, Ben-Yehuda H, Peralta Ramos JM, Castellani G, Ferrera S, Schwartz M. 2020. IFN-γ signaling at the brain’s choroid plexus epithelium is pivotal in Alzheimer’s disease PD-L1 immunotherapy. in preparation
4. Habib N, McCabe C, Medina S, Varshavsky M, Kitsberg D, Dvir-Szternfeld R, Green G, Dionne D, Nguyen L, Marshall JL, Chen F, Zhang F, Kaplan T, Regev A, Schwartz M. 2020. Disease-associated astrocytes in Alzheimer’s disease. Nat Neurosci Submitted
We expect that our studies will accomplish all their original objectives. In addition, we expect to attain human data that support boosting systemic immunity to help the brain resist AD and dementia; we have preliminary results showing that patients exhibit a state of immune suppression that interferes with their ability to cope with the disease.