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

Rosenzweig, Neta; Dvir-Szternfeld, Raz; Tsitsou-Kampeli, Afroditi; Keren‐Shaul, Hadas; Ben-Yehuda, Hila; Weill-Raynal, Pierre; Cahalon, Liora; Kertser, Alexander; Baruch, Kuti; Amit, Ido; Weiner, Assaf; Schwartz, Michal

doi:10.1038/s41467-019-08352-5

Cited by 135 publications

(154 citation statements)

References 84 publications

(119 reference statements)

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“…Tregs are CD4 positive T-lymphocyte subsets that can maintain peripheral immune tolerance [25,46,47]. Previous and our studies have reported elevated Treg counts in AD patients and an Aβ-driven AD mouse model [17,27,48], supporting the notion that aging and AD are characterized by immune tolerance and/or immune senescence [13,49]. In the present study, the systemic reduction in peripheral Tregs after the IIV treatment was associated with the mitigation of the disease pathology and cognitive impairments.…”

Section: Discussionsupporting

confidence: 84%

Influenza vaccination in early Alzheimer’s disease rescues amyloidosis and ameliorates cognitive deficits in APP/PS1 mice by inhibiting regulatory T cells

Yang

Xing

et al. 2020

J Neuroinflammation

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Background: Alzheimer's disease (AD) is a neurodegenerative disorder strongly correlated with a dysfunctional immune system. Our previous results demonstrated that inactivated influenza vaccine (IIV) facilitates hippocampal neurogenesis and blocks lipopolysaccharide (LPS)-induced cognitive impairment. However, whether IIV improves cognitive deficits in an AD mouse model remains unclear. In addition, early interventions in AD have been encouraged in recent years. Here, we investigated whether IIV immunization at the preclinical stage of AD alters the brain pathology and cognitive deficits in an APP/ PS1 mouse model. Methods: We assessed spatial learning and memory using Morris water maze (MWM). The brain β-amyloid (Aβ) plaque burden and activated microglia were investigated by immunohistochemistry. Furthermore, flow cytometry was utilized to analyze the proportions of Treg cells in the spleen. A cytokine antibody array was performed to measure the alteration of cytokines in the brain and peripheral immune system. Results: Five IIV immunizations activated microglia, reduced the Aβ burden and improved the cognitive impairment. Simultaneously, the IIV-induced immune response broke peripheral immunosuppression by reducing Foxp3 + regulatory T cell (Treg) activities, whereas the restoration of Treg level in the periphery using all-trans retinoic acid (ATRA) blunted the protective effects of IIV on Aβ burden and cognitive functions. Interestingly, IIV immunization might increase proinflammatory and anti-inflammatory cytokine expression in the brain of APP/PS1 mice, enhanced microglial activation, and enhanced the clustering and phagocytosis of Aβ, thereby creating new homeostasis in the disordered immune microenvironment. Conclusions: Altogether, our results suggest that early multiple IIV immunizations exert a beneficial immunomodulatory effect in APP/PS1 mice by breaking Treg-mediated systemic immune tolerance, maintaining the activation of microglia and removing of Aβ plaques, eventually improving cognitive deficits.

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Section: Discussionsupporting

confidence: 84%

Influenza vaccination in early Alzheimer’s disease rescues amyloidosis and ameliorates cognitive deficits in APP/PS1 mice by inhibiting regulatory T cells

Yang

Xing

et al. 2020

J Neuroinflammation

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“…With regard to the tauopathy study, Swartz and colleagues administered the same PD-1 antibody as in their Aβ model study to tauopathy mice at 8 months of age (a single intraperitoneal injection of 0.5 mg; Rosenzweig et al, 2019). The DM-hTAU mouse model has two tau mutations (K257T and P301S) and has impaired cognition and extensive tau pathology at this age (Rosenzweig et al, 2019). The single antibody injection improved cognition in a T-maze when examined 1 month later in a mixed-sex group.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, the same group that showed beneficial effects of PD-1 blockade on Aβ clearance and cognition followed up on their pioneering findings demonstrating that similar benefits could be obtained in a tauopathy model using the same PD-1 antibody and isotype control as in their original study (Rosenzweig et al, 2019). Comparable results were observed with a PD-L1 antibody.…”

Section: Introductionmentioning

confidence: 90%

Chronic PD-1 Checkpoint Blockade Does Not Affect Cognition or Promote Tau Clearance in a Tauopathy Mouse Model

Yang

Rajamohamedsait

Sandusky‐Beltran

et al. 2020

Front. Aging Neurosci.

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Programmed cell death protein 1 (PD-1) checkpoint blockade with an antibody has been shown to reduce amyloid-β plaques, associated pathologies and cognitive impairment in mouse models. More recently, this approach has shown effectiveness in a tauopathy mouse model to improve cognition and reduce tau lesions. Follow-up studies by other laboratories did not see similar benefits of this type of therapy in other amyloid-β plaque models. Here, we report a modest increase in locomotor activity but no effect on cognition or tau pathology, in a different more commonly used tauopathy model following a weekly treatment for 12 weeks with the same PD-1 antibody and isotype control as in the original Aβ-and tau-targeting studies. These findings indicate that further research is needed before clinical trials based on PD-1 checkpoint immune blockage are devised for tauopathies.

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“…In summary, our findings have demonstrated a previously unrecognized role of neuronal PD-1 in regulating learning and memory. 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 .…”

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

confidence: 99%

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

Cited by 135 publications

References 84 publications

Influenza vaccination in early Alzheimer’s disease rescues amyloidosis and ameliorates cognitive deficits in APP/PS1 mice by inhibiting regulatory T cells

Influenza vaccination in early Alzheimer’s disease rescues amyloidosis and ameliorates cognitive deficits in APP/PS1 mice by inhibiting regulatory T cells

Chronic PD-1 Checkpoint Blockade Does Not Affect Cognition or Promote Tau Clearance in a Tauopathy Mouse Model

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

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