Systemic immune‐checkpoint blockade with anti‐PD1 antibodies does not alter cerebral amyloid‐β burden in several amyloid transgenic mouse models

Latta-Mahieu, Martine; Elmer, Bradford M.; Bretteville, Alexis; Wang, Yaming; Lopez-Grancha, Mati; Goniot, Philippe; Moindrot, Nicolas; Ferrari, Paul; Blanc, Véronique; Schussler, Nathalie; Brault, Emmanuel; Roudières, Valérie; Blanchard, Véronique; Yang, Zhiyong; Barnéoud, Pascal; Bertrand, Philìppe; Roucourt, Bart; Carmans, Sofie; Bottelbergs, Astrid; Mertens, Liesbeth; Wintmolders, Cindy; Larsen, Peter H.; Hersley, Caroline; McGathey, Tyler; Racke, Margaret M.; Liu, Ling; Lu, Jirong; O’Neill, Michael; Riddell, David; Ebneth, Andreas; Nabel, Gary J.; Pradier, Laurent

doi:10.1002/glia.23260

Cited by 55 publications

(43 citation statements)

References 33 publications

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“…Previous studies showed that systemic anti-PD-1 treatment enhanced memory in mouse AD models, as a results of recruitment of immune cells (e.g., macrophages) and subsequent clearance of amyloid- plaques 3,4 . Contradictory results were also reported 5,6 . We previously demonstrated the presence of functional PD-1 in peripheral sensory neurons which regulates nociceptor excitability and pain 7 .…”

Section: Pd1-deficient Neurons Showed No Changes In Ap Amplitude and mentioning

confidence: 72%

Anti-PD-1 treatment as a neurotherapy to enhance neuronal excitability, synaptic plasticity and memory

Zhao

2019

Preprint

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Emerging immunotherapy using anti-PD-1 antibodies have improved survival in cancer patients by immune activation. Here we show that functional PD-1 receptor is present in hippocampal CA1 neurons and loss of PD-1 or local anti-PD-1 treatment with nivolumab enhances neuronal excitability and long-term potentiation in CA1 neurons, leading to enhanced learning and memory. Our findings suggest that anti-PD-1 antibody also acts as a neurotherapy for improving memory and counteracting cognitive decline.Programmed cell death protein 1 (PD-1) is an immune checkpoint inhibitor expressed by immune cells such as T cells and serves as a primary target of immunotherapy agents that fight cancer 1, 2 .New evidence suggests that anti-PD-1 also has an active role in the nervous system. Schwartz and colleagues demonstrated that systemic PD-1 blockade promoted clearance of cerebral amyloid- plaques and improve memory in mouse models of Alzheimer's disease (AD) 3, 4 through brain recruitment of peripheral macrophages in the central nervous system (CNS). However, Latta-Mahieu et al. reported that systemic anti-PD-1 treatment failed to affect Aβ pathology in 3 different models of AD 5 . Obst et al. demonstrated that PD-1 deficiency is not sufficient to induce myeloid mobilization to the brain during chronic neurodegeneration 6 . These studies suggested that anti-PD-1 treatment may improve memory through different mechanisms. Recently, we demonstrated for the first time that functional PD-1 is present in neurons 7 . Our previous study showed that PD-1 is expressed by primary sensory neurons of the peripheral nervous system (PNS) and activation of PD-1 on sensory neurons by its ligand PD-L1 suppressed nociceptor excitability and nociceptive behaviors in mice 7 . In this study, we tested the hypothesis that functional PD-1 is also present in CNS neurons. Furthermore, we postulated that Pd1 deficiency or anti-PD-1 treatment would regulate learning and memory via neuromodulation, i.e. "neurotherapy".As a first step to address the role of PD-1 in learning and memory, we compared new object learning in wild-type (WT) and knockout mice lacking Pdcd1 (Pd1 −/− ) of young adults (2-3 months, Supplementary Fig. 1a). Notably, Pd1 gene is partially deleted in Pd1 −/− mice: 2 of 5 exons (exon-2 and exon-3) were deleted, leading to a functional loss of PD-1 8 . Compared with WT mice, Pd1 −/− mice exhibited increased discrimination index at two different time points (0.5 and 24 h, P<0.05,

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Section: Pd1-deficient Neurons Showed No Changes In Ap Amplitude and mentioning

confidence: 72%

Anti-PD-1 treatment as a neurotherapy to enhance neuronal excitability, synaptic plasticity and memory

Zhao

2019

Preprint

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“…Furthermore, blockade of PD‐1 in a mouse model of Alzheimer's disease (AD) improves cognitive performance (Baruch et al, ), suggesting a broad role of NCRs in CNS pathologies. However, the effectiveness of PD‐1 blockade in AD is still not resolved (Latta‐Mahieu et al, ).…”

Section: Introductionmentioning

confidence: 99%

VISTA expression by microglia decreases during inflammation and is differentially regulated in CNS diseases

Borggrewe

Grit

Dunnen

et al. 2018

Glia

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V‐type immunoglobulin domain‐containing suppressor of T‐cell activation (VISTA) is a negative checkpoint regulator (NCR) involved in inhibition of T cell‐mediated immunity. Expression changes of other NCRs (PD‐1, PD‐L1/L2, CTLA‐4) during inflammation of the central nervous system (CNS) were previously demonstrated, but VISTA expression in the CNS has not yet been explored. Here, we report that in the human and mouse CNS, VISTA is most abundantly expressed by microglia, and to lower levels by endothelial cells. Upon TLR stimulation, VISTA expression was reduced in primary neonatal mouse and adult rhesus macaque microglia in vitro. In mice, microglial VISTA expression was reduced after lipopolysaccharide (LPS) injection, during experimental autoimmune encephalomyelitis (EAE), and in the accelerated aging Ercc1 Δ/− mouse model. After LPS injection, decreased VISTA expression in mouse microglia was accompanied by decreased acetylation of lysine residue 27 in histone 3 in both its promoter and enhancer region. ATAC‐sequencing indicated a potential regulation of VISTA expression by Pu.1 and Mafb, two transcription factors crucial for microglia function. Finally, our data suggested that VISTA expression was decreased in microglia in multiple sclerosis lesion tissue, whereas it was increased in Alzheimer's disease patients. This study is the first to demonstrate that in the CNS, VISTA is expressed by microglia, and that VISTA is differentially expressed in CNS pathologies.

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“…Administration of PD-1 antagonists stimulated IFN-γ T-cell responses, which facilitated the clearance of cerebral amyloid β and improvements in cognitive symptoms (Baruch et al, 2016). Conflicting studies, however, find that while PD1 engagement stimulated systemic immune activity; it did not lead to improvement in amyloid pathology or cognitive impairments (Latta-Mahieu et al, 2018). In addition, PD-1 immunotherapy in cancer patients also elicits pronounced immune activation, but patients commonly develop depression symptoms and cognitive impairments (Bower et al, 2009).…”

Section: Tlr4mentioning

confidence: 99%

Neuroimmune nexus of depression and dementia: Shared mechanisms and therapeutic targets

Herman

Simkovic

Pasinetti

2019

British J Pharmacology

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Dysfunctional immune activity is a physiological component of both Alzheimer's disease (AD) and major depressive disorder (MDD). The extent to which altered immune activity influences the development of their respective cognitive symptoms and neuropathologies remains under investigation. It is evident, however, that immune activity affects neuronal function and circuit integrity. In both disorders, alterations are present in similar immune networks and neuroendocrine signalling pathways, immune responses persist in overlapping neuroanatomical locations, and morphological and structural irregularities are noted in similar domains. Epidemiological studies have also linked the two disorders, and their genetic and environmental risk factors intersect along immune‐activating pathways and can be synonymous with one another. While each of these disorders individually contains a large degree of heterogeneity, their shared immunological components may link distinct phenotypes within each disorder. This review will therefore highlight the shared immune pathways of AD and MDD, their overlapping neuroanatomical features, and previously applied, as well as novel, approaches to pharmacologically manipulate immune pathways, in each neurological condition. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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Systemic immune‐checkpoint blockade with anti‐PD1 antibodies does not alter cerebral amyloid‐β burden in several amyloid transgenic mouse models

Cited by 55 publications

References 33 publications

Anti-PD-1 treatment as a neurotherapy to enhance neuronal excitability, synaptic plasticity and memory

Anti-PD-1 treatment as a neurotherapy to enhance neuronal excitability, synaptic plasticity and memory

VISTA expression by microglia decreases during inflammation and is differentially regulated in CNS diseases

Neuroimmune nexus of depression and dementia: Shared mechanisms and therapeutic targets

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