. PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model. Nat Commun. 2019 Jan 28;10(1):465. PubMed.

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  1. We read with great interest the very extensive publication from Dr. Schwartz’ group, which significantly expands on their previous work on checkpoint blockade for treating neurodegenerative diseases. Using both anti-PD-1 and now anti-PD-L1 antibodies, they demonstrate in a large series of animal studies prevention and reversion of cognitive deficits in the well-characterized 5xFAD amyloid transgenic model, and significant protection against cerebral pathology, together with the new finding of increased anti-inflammatory IL10 cytokine. Very interestingly, they extend these findings to tau transgenic animals and further analyze the possible underlying mechanisms.

    We have previously tried to generalize the checkpoint blockade concept to other amyloid transgenic mouse models, with different genetic backgrounds, and in three different animal facilities in pharmaceutical companies. While the checkpoint blockade was confirmed in the periphery in one case, collectively we could not observe a significant impact on brain amyloid pathology in any model (Latta-Mahieu et al., 2018). Experimental conditions cannot be identical (discussed in detail in Latta-Mahieu et al.), and according to Rosenzweig et al. it is indeed of outmost importance to “optimize treatments with the tested antibody in each animal model at each facility.”

    We note that in the two publications from Dr. Schwartz, xenogenic rat anti-PD1 or anti PD-L1 and human anti-PD-L1 antibodies are used and most recently at significant doses, 0.5 and 1.5 mg per mouse. Those, together with the concomitant checkpoint blockade, could participate in enhancing peripheral immune responses and the mobilization of innate immunity in brain. It would be important that such potential “sensitizing/potentiating” factors be elucidated in the future.

    We welcome and congratulate Dr. Schwartz’s group on this new publication and are looking forward to more teams in the world generalizing the checkpoint blockade concept for treating neurodegenerative diseases.

    References:

    . Systemic immune-checkpoint blockade with anti-PD1 antibodies does not alter cerebral amyloid-β burden in several amyloid transgenic mouse models. Glia. 2018 Mar;66(3):492-504. Epub 2017 Nov 14 PubMed.

    View all comments by Andreas Ebneth
  2. With regard to Latta-Mahieu et al., 2018, I am confident that the three groups that published this paper would have been able to repeat the positive effect of anti-PD-1 antibody on plaque burden, if they had calibrated the antibody and the treatment protocol in the mouse model that they used, and taken into account the different stages of the disease. The manuscript describes three single experiments, employing animal models that are different from those used in either of our papers. Below, I elaborate on the factors that could explain the failure to detect a decrease in plaque burden, the only read-out that was used to monitor the treatment effect.

    The target of the treatment with anti-PD-1 or anti-PD-L1 is not directed against β-amyloid plaques, but rather, this therapy evokes an immunological pathway that starts in the immune system and facilitates, in synergy with inflammatory cues coming from the brain, the recruitment of immune cells to the brain, together leading to multiple effects that ultimately result in cognitive improvement and neuroprotection. Accordingly, the beneficial effect of the treatment on disease modification is an outcome of the modulation of many processes that contribute to disease escalation; these include, but are not limited to, the clearance of amyloid plaques. In contrast to a treatment that is specifically directed against amyloid pathology, with the primary goal of reducing plaques, and which may or may not affect cognitive performance, in the case of immune checkpoint blockade, the beneficial effect is an outcome of several events that are affected by the therapy, the primary one being immune modulation.  

    Our first paper (Baruch et al., 2016) introduced the concept of adopting immune checkpoint blockade for treating AD, by reporting results of a single dose of anti-PD-1 antibody in 5xFAD mice. In order to generalize the phenomenon, further experiments were needed, including those addressing the mechanism, optimization of the dose/regimen, and testing in additional mouse models, which are all presented in our most recent publication (Rosenzweig et al., 2019). 

    We found that the effect of the antibody is dependent on the dose, and its affinity. Moreover, we found that elevation of IFN-γ, indicating peripheral engagement, is an essential response to the treatment, but is not sufficient. Thus, dosages that were sufficient to induce a peripheral response were insufficient to evoke a central one. In line with that observation, we found that the peripheral immune response can be evoked in wild-type animals as well, though there is no effect on monocyte infiltration and immune activity in their brains, suggesting that IFN-γ is important, but is not a valid marker of efficacy on disease progression of this treatment. In addition, in animal models of dementia, which show no plaque burden, treatment using the correct dose and timing resulted in improved cognition and reduced Tau pathology.

    In Latta-Mathieu et al., 2018, results from three different facilities were presented, which summarize three single experiments. Two of the three experiments reported used Fc chimeras (mIgG1) derived from the RPM1-14 anti-PD-1 antibody; importantly, it was shown that the chimeric Fc region significantly affects the pharmacokinetic profile of such antibodies (Ober et al., 2001), and obviously requires adjustment of the therapeutic dose/regimen. The only experiment which used the same antibody that our team used (Baruch et al., 2016) was carried out by Janssen using the commercially available rat IgG2a anti-PD-1 from BioXcell (clone RMP1-14; Catalog number, BE0146), but was tested on the ThyAPP/PS1 mouse model.

    In light of the above, we suspect that the lack of amyloid-β plaque clearance in all the experiments described in Latta-Mahieu et al., 2018, indicates that the authors, using a single dose, were working under sub-optimal experimental conditions. Based on our understanding of the mechanism, we are currently establishing the nature of the immunological marker of the response induced by the antibody that most closely correlates with treatment efficacy in Alzheimer’s disease modification; such a marker could be used to predict a response leading to disease modification. Until these markers are disseminated, and since the antibodies are not directed at amyloid plaque, the primary dose calibration in any mouse model or facility should be based on disease modification as measured by cognitive performance.

    References:

    . Systemic immune-checkpoint blockade with anti-PD1 antibodies does not alter cerebral amyloid-β burden in several amyloid transgenic mouse models. Glia. 2018 Mar;66(3):492-504. Epub 2017 Nov 14 PubMed.

    . PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease. Nat Med. 2016 Feb;22(2):135-7. Epub 2016 Jan 18 PubMed.

    . PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model. Nat Commun. 2019 Jan 28;10(1):465. PubMed.

    . Differences in promiscuity for antibody-FcRn interactions across species: implications for therapeutic antibodies. Int Immunol. 2001 Dec;13(12):1551-9. PubMed.

    View all comments by Michal Schwartz
  3. This paper is interesting and extends the group's previous findings. The authors show PD-1 or PD-L1 blockade improved murine AD and tauopathy models. Interestingly, they found that macrophages expressing scavenger receptors are involved in this process. However, the relationship between the PD-1/PD-L1 system, which works in T cells, and macrophage/microglial scavenger receptors has not been well-elucidated. To extend this effect observed in mice to the clinic, it is necessary to clarify the detailed mechanism of how PD-1/PD-L1 blockade reduces plaque burden. It must be cautioned that this treatment may promote neuroinflammation, like multiple sclerosis.

    View all comments by Akihiko Yoshimura
  4. Harnessing the peripheral immune system as a neuroprotective therapeutic approach to Alzheimer's disease: Discussion regarding pathways and mechanism

    Immunotherapy targeting the programmed death protein (PD)-1/PD-L1 pathway was shown to be effective in reducing disease manifestations as measured by cognitive performance and pathology in mouse models of AD and tauopathy (Baruch et al., 2016; Rosenzweig et al., 2019). The results, much as they were novel and provocative, were also met with skepticism, and evoked controversy when another group attempted to replicate these results and failed to show reduction in amyloid plaque deposition, as a single readout (Latta-Mahieu et al., 2018). Nevertheless, recently published papers from additional groups support the role of the peripheral immune system in containing AD (He et al., 2020; Yang et al., 2020), and further demonstrate that treatment directed at the peripheral immune system activates a process of repair, leading to disease modification and cognitive improvement in additional mouse models. These and other studies, cited below, are used here as a platform to explain the failure to reduce amyloid plaque burden as a single readout (Latta-Mahieu et al., 2018). 

    In the recent study by He and colleagues, systemic injection of IFN-γ in APP/PSN1 mice resulted in recruitment of monocyte-derived macrophages, enhanced cognitive performance, and reduction of disease pathology (He et al., 2020). Yang and colleagues showed that, in the APP/PSN1 mouse model, elevation of systemic immunosuppressive mechanisms (regulatory T cells) exacerbates disease progression, which could be overcome by influenza vaccination (Yang et al., 2020). Elevated immune suppression, as well as the negative effect of systemic regulatory T cells shown in this study (Yang et al., 2020), were previously documented in 5xFAD mice as well (Baruch et al., 2015). The effects of systemic IFN-γ injection on the brains of AD mice (He et al., 2020) are also consistent with the effect of short-term depletion of regulatory T-cells (Baruch et al., 2015) or of blocking the PD-1/PD-L1 pathway (Baruch et al., 2016; Rosenzweig et al., 2019), shown to be mediated through IFN-γ-producing T cells (Baruch et al., 2016). In AD, the IFN-γ-producing T cells facilitate recruitment of monocyte-derived macrophages to the diseased brain (Baruch et al., 2016; Rosenzweig et al., 2019). 

    Yang’s results are also consistent with the observed effect of immunization with Bacillus Calmette-Guérin (BCG) in APP/PS1 mice, which reduced the levels of regulatory cells, resulting in a 10-fold increase in the serum levels of IL-2, and a fivefold increase in IFN-γ (Zuo et al., 2017). Also in line with these observations, bladder cancer patients treated with BCG were significantly less likely to develop AD at any age compared with patients who were not treated with this modality (Gofrit et al., 2019). 

    In PD-1 or PD-L1 blockade (Baruch et al., 2016Rosenzweig et al., 2019), similarly to the new studies, described above (He et al., 2020; Yang et al., 2020), the effect of activation of the immune system was shown to be mediated, at least in part, through monocyte-derived macrophages. Monocyte-derived macrophages were repeatedly shown in mouse models of AD and dementia to be beneficial in coping with the disease, by reducing pathological manifestations and enhancing cognitive performance (Baruch et al., 2015; El Khoury et al., 2007; Naert and Rivest, 2011; Simard et al., 2006; Butovsky et al., 2007; Butovsky  et al., 2006; Koronyo et al., 2015; Koronyo-Hamaoui et al., 2009; Schwartz and Shechter, 2010; Greenhalgh et al., 2018; Dionisio-Santos et al., 2019; Li et al., 2020). Notably, such monocyte-derived macrophages, which were often referred to as “monocyte-derived microglia” (Simard et al., 2006; Mildner et al., 2007) or “dendritic-like cells” (Butovsky  et al., 2006), display activities distinct from those of the activated resident microglia (Yamasaki et al., 2014; Thériault  et al., 2015; Ajami et al., 2018). Thus, for example, the beneficial effect observed following blocking of PD-L1/PD-1 pathway was shown to be dependent upon enhanced recruitment to the brain of monocyte-derived macrophages expressing the scavenger receptor, MSR1 (Baruch et al., 2016; Rosenzweig et al., 2019). Myeloid cells expressing MSR1 were shown to be able to remove soluble Aβ (Frenkel et al., 2013), which includes the oligomers, the neurotoxic form of misfolded proteins (Shankar et al., 2007). Removal of these forms was shown to have a direct impact on cognitive performance and synaptic activity (Li et al., 2020), arguing in favor of boosting recruitment of immune cells to the brain (Baruch et al., 2016; Rosenzweig et al., 2019). 

    Recent studies using Trem2-/-5xFAD mice clearly show that cognitive impairment is correlated with the level of soluble Aβ, rather than with levels of insoluble amyloid deposits and plaques, and that Trem2-expressing cells mostly affect plaque pathology, but not soluble oligomers nor cognition, in mice over 6 months of age (Griciuc et al., 2019). 

    Taken, together, the reported apparent failure of anti PD-L1 treatment to show an effect on plaque burden, as a single, acute readout (Latta-Mahieu et al., 2018), can be explained based on the mechanism described above. According to our results, we propose that the effect of anti-PD-L1 or anti-PD-L1 treatment is mediated via monocyte-derived macrophages, which contribute to disease modification by removal of soluble Aβ that contain the neurotoxic oligomers, with effect on plaques or insoluble Aβ representing a secondary outcome, as reduction of Aβ oligomers should result in a fewer or smaller plaques over time.

    Accordingly, measuring plaque burden as a single readout for a treatment that is not directed at plaques is an unreliable marker of treatment effects (Latta-Mahieu et al., 2018). In all other studies in which the immune system was harnessed to treat AD, multiple parameters were measured, as summarized above. In contrast to the measurement of plaques, reduction of soluble toxic oligomers measured by biochemical assays, as well as improvement in cognitive performance, could be expected to be observed following a treatment that targets the PD-1/PD-L1 pathway (Baruch et al., 2016; Rosenzweig et al., 2019) or any similar treatment (He et al., 2020; Yang et al., 2020). Moreover, measuring plaques as a sole readout following PD-1 blockade (Latta-Mahieu et al., 2018) or of any treatment that does not directly target amyloid plaques, provides a limited measure of the efficacy, while soluble Aβ is a valid measure of disease modification, with likely relevance to the clinic.

    To date, treatment with anti-PD-L1 antibody has been repeated in five different mouse models of AD and tauopathy, demonstrating improvement of cognitive performance, reduction via monocyte-derived macrophages of the soluble forms of misfolded proteins, measured biochemically in the brain and in the CSF, and skewing the brain toward an anti-inflammatory state, with an increase in the presence of FoxP3+ regulatory T cells (unpublished data; manuscripts in preparation).

    Based on the data emerging from the novel concept of targeting the PD-1/PD-L1 pathway as an immune-therapy for AD and dementia, a biopharmaceutical company, ImmunoBrain Checkpoint, Inc. (IBC), was founded in 2015. IBC has engineered a proprietary anti-PD-L1 antibody, tailored to the specific therapy mechanism of activity in AD (which is distinct from that in cancer), with a high efficacy and superior safety profile in terms of risk of triggering an adverse autoimmune response (unpublished data). The antibody is currently in production scale-up in order to be ready for first in human clinical trial in 2021. Beyond testing of safety, markers have been established to determine antibody activity mechanism of action in the patient’s blood and CSF.

    References:

    . PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease. Nat Med. 2016 Feb;22(2):135-7. Epub 2016 Jan 18 PubMed.

    . PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model. Nat Commun. 2019 Jan 28;10(1):465. PubMed.

    . Systemic immune-checkpoint blockade with anti-PD1 antibodies does not alter cerebral amyloid-β burden in several amyloid transgenic mouse models. Glia. 2018 Mar;66(3):492-504. Epub 2017 Nov 14 PubMed.

    . Intraperitoneal injection of IFN-γ restores microglial autophagy, promotes amyloid-β clearance and improves cognition in APP/PS1 mice. Cell Death Dis. 2020 Jun 8;11(6):440. PubMed.

    . Influenza vaccination in early Alzheimer's disease rescues amyloidosis and ameliorates cognitive deficits in APP/PS1 mice by inhibiting regulatory T cells. J Neuroinflammation. 2020 Feb 19;17(1):65. PubMed.

    . Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer's disease pathology. Nat Commun. 2015 Aug 18;6:7967. PubMed.

    . Immunization with Bacillus Calmette-Guérin (BCG) alleviates neuroinflammation and cognitive deficits in APP/PS1 mice via the recruitment of inflammation-resolving monocytes to the brain. Neurobiol Dis. 2017 May;101:27-39. Epub 2017 Feb 9 PubMed.

    . Bacillus Calmette-Guérin (BCG) therapy lowers the incidence of Alzheimer's disease in bladder cancer patients. PLoS One. 2019;14(11):e0224433. Epub 2019 Nov 7 PubMed.

    . Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med. 2007 Apr;13(4):432-8. PubMed.

    . Hematopoietic CC-chemokine receptor 2-(CCR2) competent cells are protective for the cognitive impairments and amyloid pathology in a transgenic mouse model of Alzheimer's disease. Mol Med. 2011 Nov 29; PubMed.

    . Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron. 2006 Feb 16;49(4):489-502. PubMed.

    . Selective ablation of bone marrow-derived dendritic cells increases amyloid plaques in a mouse Alzheimer's disease model. Eur J Neurosci. 2007 Jul;26(2):413-6. PubMed.

    . Glatiramer acetate fights against Alzheimer's disease by inducing dendritic-like microglia expressing insulin-like growth factor 1. Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11784-9. PubMed.

    . Therapeutic effects of glatiramer acetate and grafted CD115⁺ monocytes in a mouse model of Alzheimer's disease. Brain. 2015 Aug;138(Pt 8):2399-422. Epub 2015 Jun 6 PubMed.

    . Attenuation of AD-like neuropathology by harnessing peripheral immune cells: local elevation of IL-10 and MMP-9. J Neurochem. 2009 Dec;111(6):1409-24. PubMed.

    . Systemic inflammatory cells fight off neurodegenerative disease. Nat Rev Neurol. 2010 Jul;6(7):405-10. PubMed.

    . Peripherally derived macrophages modulate microglial function to reduce inflammation after CNS injury. PLoS Biol. 2018 Oct;16(10):e2005264. Epub 2018 Oct 17 PubMed.

    . Exploiting microglial and peripheral immune cell crosstalk to treat Alzheimer's disease. J Neuroinflammation. 2019 Apr 5;16(1):74. PubMed.

    . Activated Bone Marrow-Derived Macrophages Eradicate Alzheimer's-Related Aβ42 Oligomers and Protect Synapses. Front Immunol. 2020;11:49. Epub 2020 Jan 31 PubMed.

    . Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci. 2007 Dec;10(12):1544-53. PubMed.

    . Differential roles of microglia and monocytes in the inflamed central nervous system. J Exp Med. 2014 Jul 28;211(8):1533-49. Epub 2014 Jul 7 PubMed.

    . The dynamics of monocytes and microglia in Alzheimer's disease. Alzheimers Res Ther. 2015;7(1):41. Epub 2015 Apr 15 PubMed.

    . Single-cell mass cytometry reveals distinct populations of brain myeloid cells in mouse neuroinflammation and neurodegeneration models. Nat Neurosci. 2018 Apr;21(4):541-551. Epub 2018 Mar 5 PubMed.

    . Scara1 deficiency impairs clearance of soluble amyloid-β by mononuclear phagocytes and accelerates Alzheimer's-like disease progression. Nat Commun. 2013;4:2030. PubMed.

    . Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci. 2007 Mar 14;27(11):2866-75. PubMed.

    . TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease. Neuron. 2019 Sep 4;103(5):820-835.e7. Epub 2019 Jul 10 PubMed.

    View all comments by Michal Schwartz
  5. Reproduction, Replication, and Responsibility

    I have followed with interest the correspondence that began with this report, which reviewed the work of Michal Schwartz and colleagues leveraging the PD-1/PD-L1 pathway, an important regulator of immune function, to provide neuroprotection in rodent models of amyloidopathy and tauopathy, and the subsequent commentary.

    In their Alzforum comments posted on 5 Feb 2019, Laurent Pradier and Andreas Ebneth, representatives of competing pharmaceutical companies, reported an apparent failure to replicate the originally reported rodent efficacy results in three different animal models of cerebral amyloidosis (Latta-Mahieu et al., 2018). Pradier and Ebneth admit that “experimental conditions cannot be identical,” and this was indeed the case. In the Latta-Mahieu paper, three different mouse strains were used, but interestingly, none of these groups used the 5xFAD strain used by Baruch et al. (2016) and by Rosenzweig et al. (2019) as an independent control. Thus, comparability of disease severity could not be established between their experiments and those of Rosenzweig et al. or Baruch et al. The antibodies used were not identical, and the doses used were around 60 percent of the maximally effective dose in the Baruch paper (Figure 2).

    Pradier et al. comment on the need for replication across multiple animal models to support validity of a given therapeutic antibody approach. In general, most amyloid antibodies have been tested in a single animal model; i.e. that which is favored in the laboratories of the company sponsoring their development. When tested outside the originating company, data is not always confirmatory, as in the case of gantenerumab, which was originally studied in APP751(Swedish)xPS2(N141I) transgenic mice (Bohrmann et al., 2012), and crenezumab (Adolfsson et al., 2012). Both these antibodies failed to clear plaque from the brains of Tg2576 mice in one study (Fuller et al., 2015). Interestingly, the study of Fuller et al. was also supported at least in part by a competing pharmaceutical company. On the other hand, Xing et al. (2020) recently published a study that replicated key findings from the Baruch et al., 2016, paper, this time using an APP-PS1 model and the same commercially available anti-PD1 tool antibody used by the Schwartz group.

    At the recent AAIC meeting, Baruch et al., now working at the biopharmaceutical company Immunobrain Checkpoint, presented results describing further experiments with a different anti-PD-L1 antibody in several rodent models (Baruch et al., 2020). Of note, the antibody used had been modified to ablate Fc effector function and carried a second modification that shortened its pharmacokinetic half-life.

    Baruch et al. confirmed efficacy on cognitive performance in 5xFAD mice, as well as two transgenic tauopathy models. Among other findings reported on the poster were (1) dose-dependent pharmacodynamic effects on peripheral immune markers, and (2) prolonged efficacy in a longitudinal study in DM-hTAU (K257T/P301S) transgenic mice. Treatment efficacy in this intermittent administration regimen was found to be effective for at least five months from treatment initiation, and persisted for at least eight weeks after the last injection. These results are consistent with the hypothesis that immune checkpoint inhibition activates a process of repair that is common to several experimental models independently of the underlying proteinopathy. Since most neurodegenerative disorders are believed to represent “multi-proteinopathies” (Robinson et al., 2018), this observation could augur well in predicting success going forward to the clinic.  

    Importantly, the authors demonstrated that the modifications made to the antibody’s backbone significantly reduced its propensity to precipitate early onset of autoimmune diabetes in the well-known NOD mouse model susceptible to autoimmune diabetes. This finding could prove important for future clinical trials in that it may indicate that similar modifications incorporated into the anti-human PD-L1 antibody (IBC-Ab002), currently being readied for clinical trials, would translate to an advantageous safety profile in terms of immune-related adverse effects compared to anti-PD-L1 antibodies currently in the clinic.

    In the original Alzforum commentary, reference was made to the paper by Richard Ransohoff titled “All (animal) models (of neurodegeneration) are wrong. Are they also useful?” (Ransohoff et al., 2018). In his insightful review, Ransohoff points out that our current animal models have been woefully inadequate in predicting the outcome of human clinical trials. However, he concludes by stating that: “… animal models remain extraordinarily valuable for investigating biological processes. In the drug development process, these models can also serve as the preferred testing platform for prospective pharmacodynamic biomarkers.”  

    We as a field need to come to grips with when “perfect is the enemy of good enough” and, recognizing the limits of animal model testing, agree that internally consistent datasets that (1) yield testable hypotheses and (2) biomarker findings reflecting mechanism of action in the animals that can be translated into the clinic, and (3) suggest acceptable risk-benefit in patients, can and should be tested responsibly in human clinical trials.

    Disclosure: I am a paid advisor to, and shareholder in, Immunobrain Checkpoint, and am acting as the study director for the trial mentioned here, which received a 2020 Alzheimer’s Association Part the Clouds Gates Partnership grant. 

    References:

    . Systemic immune-checkpoint blockade with anti-PD1 antibodies does not alter cerebral amyloid-β burden in several amyloid transgenic mouse models. Glia. 2018 Mar;66(3):492-504. Epub 2017 Nov 14 PubMed.

    . PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease. Nat Med. 2016 Feb;22(2):135-7. Epub 2016 Jan 18 PubMed.

    . PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model. Nat Commun. 2019 Jan 28;10(1):465. PubMed.

    . Gantenerumab: A Novel Human Anti-Aβ Antibody Demonstrates Sustained Cerebral Amyloid-β Binding and Elicits Cell-Mediated Removal of Human Amyloid-β. J Alzheimers Dis. 2012;28(1):49-69. PubMed.

    . An effector-reduced anti-β-amyloid (Aβ) antibody with unique aβ binding properties promotes neuroprotection and glial engulfment of Aβ. J Neurosci. 2012 Jul 11;32(28):9677-89. PubMed.

    . Comparing the efficacy and neuroinflammatory potential of three anti-abeta antibodies. Acta Neuropathol. 2015 Nov;130(5):699-711. Epub 2015 Oct 3 PubMed.

    . Influenza vaccine combined with moderate-dose PD1 blockade reduces amyloid-β accumulation and improves cognition in APP/PS1 mice. Brain Behav Immun. 2020 Sep 19; PubMed.

    . Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain. 2018 Jul 1;141(7):2181-2193. PubMed.

    . All (animal) models (of neurodegeneration) are wrong. Are they also useful?. J Exp Med. 2018 Dec 3;215(12):2955-2958. Epub 2018 Nov 20 PubMed.

    View all comments by Jesse Cedarbaum

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