PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease

Baruch, Kuti; Deczkowska, Aleksandra; Rosenzweig, Neta; Tsitsou-Kampeli, Afroditi; Sharif, Alaa; Matcovitch-Natan, Orit; Kertser, Alexander; David, Eyal; Amit, Ido; Schwartz, Michal

doi:10.1038/nm.4022

Cited by 320 publications

(311 citation statements)

References 26 publications

Supporting

Mentioning

296

Contrasting

Unclassified

Order By: Relevance

“…Infusion of monocytes derived from peripheral human umbilical cord blood reduces the Aβ burden and improves cognitive deficits in a mouse model of AD 46 , implying that peripheral mononuclear phagocytes have an important role in Aβ clearance. Promoting the phagocytic function of peripheral blood monocytes or promoting the recruitment of peripheral macrophages into the brain might, therefore, improve Aβ clearance in the brain 47 , although the existence of conflicting data 48 renders this approach controversial.…”

Section: Disorders Of Systemic Immunitymentioning

confidence: 99%

“…By contrast, acute systemic inflammatory responses seem to protect against AD -at least in animal models -by recruiting monocyte-derived macrophages into the brain, where they clear cerebral Aβ 47 . However, most studies in this area have not been repeated, and their results have not yet been validated in patients with biomarker-confirmed AD.…”

Section: Systemic Inflammationmentioning

confidence: 99%

See 1 more Smart Citation

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

View full text Add to dashboard Cite

The global burden of Alzheimer disease (AD), already the most common type of dementia, is expected to increase still further owing to population ageing. AD not only causes severe distress for patients and caregivers, but also results in a large economic burden on society. Current major challenges in AD include the lack of reliable biomarkers for its early diagnosis, as well as the lack of effective preventive strategies and treatments 1,2 . Thus, increased understanding of the molecular patho genesis of AD could lead to the development of improved diagnostic and therapeutic strategies.AD is conventionally regarded as a CNS disorder. However, increasing experimental, epidemiological and clinical evidence has suggested that manifestations of AD extend beyond the brain. These systemic alterations might not be simply secondary effects of the cerebral degeneration seen in AD, but could reflect under lying processes linked to progression of the disease. AD pathogenesis is complex, involving abnormal amyloid-β (Aβ) metabolism, tau hyperphosphorylation, oxidative stress, reactive glial and microglial changes, and other pathological events. Given that Aβ is a major hallmark of AD and a fertile area of research in this disease, this Review focuses on the systemic role of Aβ in AD. We discuss the communication between peripheral and central pools of Aβ, and describe interactions between systemic abnormalities and AD pathogenesis in the brain. We review emerging findings of associations between systemic abnormalities and Aβ metabolism, and describe how these associations might interact with or reflect on the central pathways of Aβ production and clearance. On the basis of these findings, we suggest that interactions between the brain and the periphery might have a crucial role in the development and progression of AD. Aβ biogenesis and catabolismA steady accrual of data from laboratories and clinics is providing increasing support for the concept that an imbalance between the production and clearance of Aβ is a very early (and often initiating) factor in AD 3 . Normal metabolism of Aβ and maintenance of the homeostatic balance between Aβ production and clearance is, therefore, essential to maintain brain health. In fact, physiological metabolism of Aβ occurs not only in the brain but also in the periphery, and communication between these regions is possible (FIG. 1). Central and peripheral production of AβAβ is derived from the proteolytic cleavage of amyloid precursor protein (APP), which is expressed not only in brain cells, including neurons, astrocytes and microglia, but also in peripheral organs and tissues, such as the Abstract | Alzheimer disease (AD) is the most common type of dementia, and is currently incurable; existing treatments for AD produce only a modest amelioration of symptoms. Research into this disease has conventionally focused on the CNS. However, several peripheral and systemic abnormalities are now understood to be linked to AD, and our understanding of how these alterations contribute to AD is becom...

show abstract

Section: Disorders Of Systemic Immunitymentioning

confidence: 99%

Section: Systemic Inflammationmentioning

confidence: 99%

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Very recently, a new study offered evidence that PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of AD 149 . It appears that both systemic and local inflammation plays double-sword roles.…”

Section: Molecular and Genetic Inflammation Network Underlying Neuromentioning

confidence: 99%

Molecular and genetic inflammation networks in major human diseases

et al. 2016

View full text Add to dashboard Cite

It has been well-recognized that inflammation alongside tissue repair and damage maintaining tissue homeostasis determines the initiation and progression of complex diseases. Albeit with the accomplishment of having captured most critical inflammation involved molecules, genetic susceptibilities, epigenetic factors, and environmental exposures, our schemata on role of inflammation in complex disease, remain largely patchy, in part due to the success of reductionism in terms of research methodology per se. Omics data alongside the advances in data integration technologies have enabled reconstruction of molecular and genetic inflammation networks which shed light on the underlying pathophysiology of complex diseases or clinical conditions. Given the proven beneficial role of anti-inflammation in coronary heart disease as well as other complex diseases and immunotherapy as a revolutionary transition in oncology, it becomes timely to review our current understanding of the inflammation molecular and genetic networks underlying major human diseases. In this Review, we first briefly discuss the complexity of infectious diseases and then highlight recently uncovered molecular and genetic inflammation networks in other major human diseases including obesity, type II diabetes, coronary heart disease, late onset Alzheimer Disease, Parkinson disease, and sporadic cancer. The commonality and specificity of these molecular networks are addressed in the context of genetics based on genome-wide association study (GWAS). The double-sword role of inflammation, such as how the aberrant type 1 and/or type 2immunity leads to chronic and severe clinical conditions, remains open in terms of the inflammasome and the core inflammatome network features. Increasingly available large Omics and clinical data in tandem with systems biology approaches have offered an exciting yet challenging opportunity toward reconstruction of more comprehensive and dynamic molecular and genetic inflammation networks, which hold a great promise in transiting network snapshots to video-style multi-scale interplays of disease mechanisms, in turn leading to effective clinical intervening.

show abstract

“…nivolumab and pembrolizumab among others in the pipeline (3,6). In addition, the more complex functions of PD-1 are evidenced by its important role in the generation and activity of induced regulatory T cells (7)(8)(9), its high expression on follicular helper CD4 ϩ T cells (10), the improved cognitive performance in an Alzheimer's mouse model with PD-1 blockade (11), and its expression and growthpromoting effect on certain tumor cells (12).…”

mentioning

confidence: 99%

In situ and in silico kinetic analyses of programmed cell death-1 (PD-1) receptor, programmed cell death ligands, and B7-1 protein interaction network

Cheng

Tilevik

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Norma AllewellProgrammed cell death-1 (PD-1) is an inhibitory receptor with an essential role in maintaining peripheral tolerance and is among the most promising immunotherapeutic targets for treating cancer, autoimmunity, and infectious diseases. A complete understanding of the consequences of PD-1 engagement by its ligands, PD-L1 and PD-L2, and of PD-L1 binding to B7-1 requires quantitative analysis of their interactions at the cell surface. We present here the first complete in situ kinetic analysis of the PD-1/PD-ligands/B7-1 system. Consistent with previous solution measurements, we observed higher in situ affinities for human (h) than murine (m) PD-1 interactions, stronger binding of hPD-1 to hPD-L2 than hPD-L1, and comparable binding of mPD-1 to both ligands. However, in contrast to the relatively weak solution affinities, the in situ affinities of PD-1 are as high as those of the T cell receptor for agonist pMHC and of LFA-1 (lymphocyte function-associated antigen 1) for ICAM-1 (intercellular adhesion molecule 1) but significantly lower than that of the B7-1/CTLA-4 interaction, suggesting a distinct basis for PD-1-versus CTLA-4-mediated inhibition. Notably, the in situ interactions of PD-1 are much stronger than that of B7-1 with PD-L1. Overall, the in situ affinity ranking greatly depends on the on-rate instead of the off-rate. In silico simulations predict that PD-1/PD-L1 interactions dominate at interfaces between activated T cells and mature dendritic cells and that these interactions will be highly sensitive to the dynamics of PD-L1 and PD-L2 expression. Our results provide a kinetic framework for better understanding inhibitory PD-1 activity in health and disease.PD-1 2 (CD279) is an immune checkpoint receptor expressed mainly on activated T cells and B cells. Its primary function is to maintain peripheral tolerance within the adaptive immune system. PD-1 deficiency results in spontaneous development of autoimmunity in mouse models (1, 2), and polymorphism of its gene PDCD1 in humans is associated with various autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, type I diabetes, etc., among different populations (3). High surface expression of PD-1 has also been found to be a hallmark of T cell exhaustion, where antigen-specific CD8 ϩ T cells lose their ability to combat tumor cells or virus-infected cells (4, 5). Antibody blockade of the PD-1 pathway is able to restore the effector functions of exhausted CD8 ϩ T cells for tumor or viral clearance, and this approach is emerging as a promising immunotherapeutic strategy to treat a wide range of cancer and infectious diseases, e.g. nivolumab and pembrolizumab among others in the pipeline (3, 6). In addition, the more complex functions of PD-1 are evidenced by its important role in the generation and activity of induced regulatory T cells (7-9), its high expression on follicular helper CD4 ϩ T cells (10), the improved cognitive performance in an Alzheimer's mouse model with PD-1 blockade (11), and its expression ...

show abstract

PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease

Cited by 320 publications

References 26 publications

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

Molecular and genetic inflammation networks in major human diseases

In situ and in silico kinetic analyses of programmed cell death-1 (PD-1) receptor, programmed cell death ligands, and B7-1 protein interaction network

Contact Info

Product

Resources

About