We found significantly higher protein levels of IL-1 in the hippocampi of DM-hTAU mice relative to age-matched wild-type littermates, and a significant reduction following anti-PD-L1?antibody treatment relative to untreated, or IgG2b-treated DM-hTAU mice (Fig.?3l). comparable efficacy?to that of PD-1 blocking in disease modification, in both animal models of AD and of tauopathy. Targeting PD-L1 in a?tau-driven disease model resulted in increased immunomodulatory monocyte-derived macrophages within the brain parenchyma. Single cell RNA-seq revealed that this homing macrophages expressed unique scavenger molecules including macrophage scavenger receptor 1 (MSR1), which was shown here to be?required for the effect of?PD-L1 blockade in?disease modification. Overall, our results demonstrate that immune checkpoint blockade targeting the PD-1/PD-L1 pathway leads to modification of common factors that go awry in AD and dementia, and thus can potentially provide an immunotherapy to help combat these diseases. Introduction Alzheimers disease (AD) is a highly heterogeneous disease, in which several genetic risk factors have already been identified1C4. Yet, despite decades of research, therapies that individually target such identified risk factors have largely failed5C9, suggesting that addressing single disease-associated factors, even critical ones, while possibly effective, is usually apparently insufficient for modifying the disease. Over the last two decades, Iohexol it became clear that systemic immune cells are important players in brain maintenance and repair, with implications to brain aging and neurodegenerative conditions10C15. Moreover, systemic immune deficiency has been associated with cognitive dysfunction13, behavioral dysfunction14 and reduced ability to cope with neurodegenerative conditions, including Amyotrophic lateral sclerosis (ALS)16 and AD17. Accordingly, boosting recruitment of monocyte-derived macrophages to sites of brain pathology in several mouse models of AD, resulted in reduced brain pathology, in general, and reduced plaque burden, in particular18C24. We previously reported that recruitment of monocyte-derived macrophages is dependent on systemic availability of IFN–producing CD4+ T cells25,26. In line with this obtaining, several independent studies have highlighted the unfavorable role of overwhelming?systemic immunosuppressive cells, or of immunosuppressive cytokines in AD pathology26C28. These results as well as others led us to Iohexol envision that empowering the peripheral immune system would facilitate the recruitment of disease-modifying leukocytes to the brain parenchyma. Testing this premise in an amyloid-beta-driven AD mouse model, 5XFAD29, led us to discover that transient reduction of systemic immune suppression (by reducing systemic levels of FoxP3 regulatory T cells or by blocking the inhibitory programmed-death (PD)-1 immune checkpoint pathway), could lead to Alzheimer?s?disease modification26,30. Here, we hypothesized that immune checkpoint blockade might activate common immune-dependent repair mechanisms, ?irrespective?of the primary?cause of the disease pathology. We found that targeting PD-1 or its TNFSF8 PD-L1 ligand could change AD pathology in a mouse model of amyloid pathology, 5XFAD, as well as in an animal model of tau pathology, expressing the human-tau gene with two mutations associated with frontotemporal dementia (DM-hTAU)31. In DM-hTAU mice, systemic administration of anti-PD-L1 blocking?antibody mitigated?both cognitive deficits as well as pathological manifestations of the disease, and altered the immunological milieu of the brain. Moreover, single-cell RNA-Seq revealed a unique reparative role of the infiltrating monocyte-derived macrophages, which substantiated their beneficial role in the anti-PD-L1?Alzheimer’s disease therapy. Results Iohexol Monthly treatment with anti-PD-1 antibody delays cognitive decline and supports neuronal rescue In our recent study, we showed that in male 5XFAD mice, administration of two injections of anti-PD-1 antibody (0.25?mg at a 3-day interval) resulted, 1 month later, in reversal of cognitive loss and modification of some of the pathological features of AD30. Here, we first repeated this experiment in female mice to ensure that the treatment is effective in both genders, and also tested if a single dose of 0.5?mg anti-PD-1 antibody could be as effective as two injections of Iohexol 0.25?mg given in at?3-day interval30. To this end, 5XFAD female mice were treated with either two injections of 0.25?mg or with a single injection of 0.5?mg of anti-PD-1. Spatial learning/memory space function was assessed 1 month later on using the radial arm water maze (RAWM) task. Both treatment regimens offered a similar beneficial effect on cognitive overall performance, relative to?treatment with isotype-matched IgG2a control antibody (Supplementary Fig.?1). Consequently, for our subsequent experiments, we used a single injection of the antibody in the indicated dose, rather than a break up dose, and worked with both male and female mice, as indicated throughout this study. To examine whether the beneficial effect associated with PD-1 blockade could delay cognitive decrease, we treated a cohort of 5XFAD mice (female and male, in equivalent proportions in all tested groups; approximately 3.5 months of age) with anti-PD-1?antibody, and continued the treatment once a month for an additional 2 weeks (a single injection of 0.5?mg once every 4 weeks) (Fig.?1a). We evaluated these mice for his or her spatial learning and memory space overall performance twice, first at 5. 5 weeks and consequently at 6.5 months of age (changing the cues for the second RAWM test). Our results exposed that while at the age of 5.5 months, the control IgG-treated animals showed residual learning/memory skills with this maze, and thus exhibited some learning within the last trial of the second day (Fig.?1b), by the age of 6.5.