Neutrophils promote Alzheimer's disease–like pathology and cognitive decline via LFA-1 integrin

Zenaro, Elena; Pietronigro, Enrica Caterina; Bianca, Vittorina Della; Piacentino, Gennj; Marongiu, Laura; Budui, Simona; Turano, Ermanna; Rossi, Barbara; Angiari, Stefano; Dusi, Silvia; Montresor, Alessio; Carlucci, Tommaso; Nanì, Sara; Tosadori, Gabriele; Calciano, Lucia; Catalucci, Daniele; Berton, Giorgio; Bonetti, Bruno; Constantin, Gabriela

doi:10.1038/nm.3913

Cited by 619 publications

(793 citation statements)

References 61 publications

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“…Our data confirm that IgG alone is sufficient to increase phagocytosis in vitro and that delivery of IgG directly to the brains of Rag-5xfAD mice or into circulation via adoptive transfer can induce plaque clearance. Our study therefore adds to a growing area of research that highlights the importance of the peripheral immune system in CNS function and AD (17,18), and demonstrates the need to better understand how these peripheral cell populations act in concert with microglia to influence the CNS in both normal and diseased conditions.…”

Section: Discussionmentioning

confidence: 83%

“…However, the adaptive and innate immune systems rarely function independently of each other, and thus cross talk between peripheral and central immunity such as cytokine and chemokine signaling likely plays an important albeit understudied role in AD. In support of this notion, two recent studies demonstrated profound effects of peripherally derived neutrophils and T-regulatory cells (Tregs) on AD pathogenesis (17,18). Despite this exciting recent progress, many of the mechanisms and actions of other peripheral immune cell populations in AD remain unknown, and thus a great a deal of additional study is needed.…”

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confidence: 99%

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The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

Marsh

Abud

Lakatos

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

334

287

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The innate immune system is strongly implicated in the pathogenesis of Alzheimer's disease (AD). In contrast, the role of adaptive immunity in AD remains largely unknown. However, numerous clinical trials are testing vaccination strategies for AD, suggesting that T and B cells play a pivotal role in this disease. To test the hypothesis that adaptive immunity influences AD pathogenesis, we generated an immune-deficient AD mouse model that lacks T, B, and natural killer (NK) cells. The resulting "Rag-5xfAD" mice exhibit a greater than twofold increase in β-amyloid (Aβ) pathology. Gene expression analysis of the brain implicates altered innate and adaptive immune pathways, including changes in cytokine/chemokine signaling and decreased Ig-mediated processes. Neuroinflammation is also greatly exacerbated in Rag-5xfAD mice as indicated by a shift in microglial phenotype, increased cytokine production, and reduced phagocytic capacity. In contrast, immune-intact 5xfAD mice exhibit elevated levels of nonamyloid reactive IgGs in association with microglia, and treatment of Rag-5xfAD mice or microglial cells with preimmune IgG enhances Aβ clearance. Last, we performed bone marrow transplantation studies in Rag-5xfAD mice, revealing that replacement of these missing adaptive immune populations can dramatically reduce AD pathology. Taken together, these data strongly suggest that adaptive immune cell populations play an important role in restraining AD pathology. In contrast, depletion of B cells and their appropriate activation by T cells leads to a loss of adaptiveinnate immunity cross talk and accelerated disease progression.is the leading cause of age-related neurodegeneration, affecting over 5.2 million people in the United States alone (1). Pathologically, AD is characterized by two hallmark protein aggregates, amyloid-β (Aβ) plaques and neurofibrillary tangles, that are accompanied by neuroinflammation, including microgliosis, elevated cytokine production, and activation of complement pathways (2-5). Initially, microglia respond to and surround plaques, degrading Aβ by phagocytosis (for review, see refs. 6-8). However, chronic activation of these cells shift microglia to a more proinflammatory and less phagocytic state (9, 10). Although much of the data implicating microglia in AD has come from neuropathological investigation, recent genome-wide association studies have provided the first genetic evidence (to our knowledge) linking microglia dysfunction to AD, with the discovery of risk polymorphisms in several immune system genes: CR1, TREM2, CD33, HLA-DRB5, MS4A6A, and ABCA7 (8,(11)(12)(13)(14)(15).In contrast to the field's increasing understanding of the role of innate immunity in AD, comparatively little is known about whether the adaptive immune system might also influence AD. Those studies that have examined these peripheral populations have largely focused on questions about their potential as biomarkers or their role in active Aβ immunization (3, 16). However, the adaptive and innate immune systems rarely fu...

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Section: Discussionmentioning

confidence: 83%

mentioning

confidence: 99%

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

Marsh

Abud

Lakatos

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

334

287

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“…Accumulations of Aβ in the periphery can similarly be phagocytosed by monocytes and neutrophils in the blood, and by macrophages in tissues 41 . Of note, in transgenic mice with AD, expression of Aβ scavenger receptors and Aβ-degrading enzymes in circulating mononuclear phagocytes decreases substantially as these mice age 42 , and the phagocytic functions of these cells are impaired in both mice and humans with AD [43][44][45] .…”

Section: Disorders Of Systemic Immunitymentioning

confidence: 99%

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

et al. 2017

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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...

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“…Using transgenic AD models, the extravasation of neutrophils into brain parenchyma to areas of amyloid plaques has been demonstrated [14,15]. At this time it is not known how IL-8 signaling contributes to the patterns of neutrophil infiltration in the AD animal models.…”

Section: Introductionmentioning

confidence: 99%

Chemokine Interleukin-8 (IL-8) in Alzheimer’s and Other Neurodegenerative Diseases

McLarnon¹

2016

J Alzheimers Dis Parkinsonism

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Neutrophils promote Alzheimer's disease–like pathology and cognitive decline via LFA-1 integrin

Cited by 619 publications

References 61 publications

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

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

Chemokine Interleukin-8 (IL-8) in Alzheimer’s and Other Neurodegenerative Diseases

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