Functional Impairment of Microglia Coincides with Beta-Amyloid Deposition in Mice with Alzheimer-Like Pathology

Krabbe, Grietje; Halle, Annett; Matyash, Vitali; Rinnenthal, Jan Leo; Eom, Gina D.; Bernhardt, Ulrich; Miller, Kelly R.; Prokop, Stefan; Kettenmann, Helmut; Heppner, Frank L.

doi:10.1371/journal.pone.0060921

Cited by 379 publications

(330 citation statements)

References 40 publications

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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] . 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.…”

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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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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“…However, it remains unclear whether microglia phagocytose Aβ fibrils in vivo (Prokop, Miller, & Heppner, 2013). Moreover, microglial function is impaired in a progressive, Aβ‐dependent manner, as shown by a decrease in the phagocytosis of beads in a mouse model of AD (Krabbe et al, 2013). Paradoxically, microglia impairment might be sustained by inflammatory cytokines, which suggests that AD pathology can be accelerated through this vicious circle (Heppner et al, 2015).…”

Section: Cellular Changes In Aging and Admentioning

confidence: 99%

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

et al. 2018

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Alzheimer's disease is the most prevalent cause of dementia, which is defined by the combined presence of amyloid and tau, but researchers are gradually moving away from the simple assumption of linear causality proposed by the original amyloid hypothesis. Aging is the main risk factor for Alzheimer's disease that cannot be explained by amyloid hypothesis. To evaluate how aging and Alzheimer's disease are intrinsically interwoven with each other, we review and summarize evidence from molecular, cellular, and system level. In particular, we focus on study designs, treatments, or interventions in Alzheimer's disease that could also be insightful in aging and vice versa.

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“…Despite the notion that the morphological transformation is a common indicator of their activation, the functional changes can be quite distinct with respect to the type of pathology and the pathological progression (Hanisch and Kettenmann 2007). We have recently demonstrated that (morphologically activated) microglial cells in a mouse model of Alzheimer's disease decrease their phagocytic activity coincident with the appearance of plaques (Krabbe et al 2013). …”

Section: Introductionmentioning

confidence: 99%

The subpopulation of microglia sensitive to neurotransmitters/neurohormones is modulated by stimulation with LPS, interferon-γ, and IL-4

Pannell

Szulzewsky

Matyash

et al. 2014

Glia

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The subpopulation of microglia sensitive to neurotransmitters/neurohormones is modulated by stimulation with LPS, interferon-γ, and IL-4Pannell, M., Szulzewsky, F., Matyash, V., Wolf, S.A., Kettenmann, H. This is the accepted version of the following article:Pannell, M., Szulzewsky, F., Matyash, V., Wolf, S.A., Kettenmann, H. The subpopulation of microglia sensitive to neurotransmitters/neurohormones is modulated by stimulation with LPS, interferon-{gamma}, and IL-4. Glia 62(5): 667-679, 2014., which has been published in final form at http://dx.doi.org/10.1002/glia. Main PointsWe found that subpopulations of acutely isolated or cultured microglia express distinct neurohormone and neurotransmitter receptors. We observed that these subpopulations change in cultured microglial cells when activated indicating that microglia comprise a highly heterogeneous population of cells with respect to their chemosensitivity. Key WordsNeurotransmitter receptor, neurohormone receptor, microglia, IFN-gamma, LPS, IL-4 3 AbstractNeurotransmitters/-hormones have recently been identified as factors controlling the function of microglia, the immune competent cells of the central nervous system. In this study we compared the responsiveness of microglia to neurotransmitters/-hormones. We freshly isolated microglia from healthy adult C57Bl/6 mice and found that only a small fraction (1 -20 %) responded to the application of endothelin, histamine, substance P, serotonin, galanin, somatostatin, angiotensin II, vasopressin, neurotensin, dopamine or nicotine.In cultured microglia from neonatal and adult mice, a similarly small population of cells responded to these neurotransmitters/-hormones. To induce a pro-inflammatory phenotype, we applied LPS or IFN-γ to the cultures for 24 h. Several of the responding populations increased, but there was no uniform pattern when comparing adult with neonatal microglia or LPS with IFN-γ treatment. IL-4 as an anti-inflammatory substance increased the histamine, substance P and somatostatin sensitive populations only in microglia from adult, but not in neonatal cells. We also found that the expression of different receptors was not strongly correlated indicating that there are many different populations of microglia with a distinct set of receptors. Our results demonstrate that microglial cells are a heterogeneous population with respect to their sensitivity to neurotransmitters/-hormones and that they are more responsive in defined activation states.4

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Functional Impairment of Microglia Coincides with Beta-Amyloid Deposition in Mice with Alzheimer-Like Pathology

Cited by 379 publications

References 40 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

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

The subpopulation of microglia sensitive to neurotransmitters/neurohormones is modulated by stimulation with LPS, interferon-γ, and IL-4

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