PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model

Alzheimer's disease (AD) is a heterogeneous disorder with multiple etiologies. Harnessing the immune system by blocking the programmed cell death receptor (PD)-1 pathway in an amyloid beta mouse model was shown to evoke a sequence of immune responses that lead to disease modification. Here, blocking PD-L1, a PD-1 ligand, was found to have similar 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 the 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. Overall design: Cell populations were sorted with FACSAriaIII (BD Biosciences, San Jose, CA). Prior to sorting, all samples were filtered through a 40-µm nylon mesh. For the isolation of monocytes-derived macrophages, samples were gated for CD45high and CD11bhigh (Brilliant-violet-421, 1:150, 30-F11, Biolegend Inc. San Diego, CA; APC CD11b, 1:100, M1/70, eBioscience), while excluding doublets. Isolated cells were single cell sorted into 384-well cell capture plates containing 2?µL of lysis solution and barcoded poly(T) reverse-transcription (RT) primers for single-cell RNA-seq84. Four empty wells were designated in each 384-well plate as a no-cell control during data analysis. Immediately after sorting, each plate was spun down to ensure cell immersion into the lysis solution, snap frozen on dry ice, and stored at -80?°C until processing. Single-cell libraries were prepared as previously described73. In brief, mRNA from cells sorted into cell capture plates was barcoded, converted into cDNA, and pooled using an automated pipeline. The pooled sample was then linearly amplified by T7 in vitro transcription, and the resulting RNA was fragmented and converted into a sequencing-ready library by tagging the samples with pooled barcodes and Illumina sequences during ligation, RT, and PCR. Each pool of cells was tested for library quality, and concentration was assessed, as described73.

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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