Phagocytosis in the Brain: Homeostasis and Disease

Galloway, Dylan A.; Phillips, Alexandra; Owen, David R.; Moore, Craig S.

doi:10.3389/fimmu.2019.00790

Cited by 233 publications

(219 citation statements)

References 219 publications

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“…Importantly, other research groups have suggested the proliferative and neurite-outgrowth properties exhibited by microglia represent a promising potential therapeutic target to repair injuries or treat degenerative disorders of affecting the central nervous system (CNS) 50 . This is consistent with their role during development, when dynamic patterns of morphological change during facilitate the formation of complex CNS and brain neuronal networks 51 , as well as their established roles in synapse monitoring 52 , apoptotic-debris clearing, and synaptic pruning 53 , all of which are required to maintain normal brain development and CNS homeostasis 54 . Microglia rapidly alter their morphology and function in response to changes in the brain microenvironment 55 .…”

Section: Discussionsupporting

confidence: 67%

Porcine liver decomposition product-derived lysophospholipids promote microglial activation in vitro

Tsukahara

Haniu

Uemura

et al. 2020

Sci Rep

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cognitive impairments such as dementia are common in later life, and have been suggested to occur via a range of mechanisms, including oxidative stress, age-related changes to cellular metabolism, and a loss of phospholipids (pLs) from neuronal membranes. pLs are a class of amphipathic lipids that form plasma membrane lipid bilayers, and that occur at high concentrations in neuronal membranes. our previous study suggested that a porcine liver decomposition product (pLDp) produced via protease treatment may improve cognitive function at older ages, by acting as a rich source of pLs and lysophospholipids (LPLs); however, its specific composition remains unclear. Thus, the present study used a novel liquid chromatography electrospray ionization tandem mass spectrometric (Lc-MS/MS) protocol to identify the major PLs and LPLs in PLDP. Furthermore, it assessed the effect of identified LPLs on microglial activation in vitro, including cell shape, proliferation, and cell morphology. the results of the conducted analyses showed that pLDp and pLDp-derived LpLs concentrationdependently modulate microglial activation in vitro. in particular, lysophosphatidylcholine (Lpc) concentration-dependently promotes cell morphology, likely via effects mediated by the enzyme autotaxin (AtX), since inhibiting AtX also promoted cell morphology, while conversely, increasing AtX production (via treatment with high levels of LPC) abolished this effect. These findings suggest that Lpc is likely neuroprotective, and thus, support the importance of further research to assess its use as a therapeutic target to treat age-related cognitive impairments, including dementia.Rapid population aging and age-related disease represent an increasing global health-care burden. Dementias are the most common cause of significant late-onset cognitive decline, and affect approximately 50 million people worldwide, with nearly 10 million new cases diagnosed annually 1 . There are many different forms of dementia; for example, Alzheimer's disease is the most common form, and contributes to 60-70% of cases. Other major forms include vascular and Lewy body dementia, and a group of diseases that together comprise frontotemporal dementia 2 . Patients with mild cognitive impairment (MCI) are at risk of developing dementia; however, in some individuals, MCI reverts to normal cognition or remains stable. While clinical studies are currently being conducted to identify novel treatments to improve symptoms and/or prevent or delay the progression of MCI to dementia, no drugs or other treatments have yet been specifically approved for MCI. Lipids are increasingly recognized for their roles in neuronal function in the brain 3,4 ; for example, the lipid fraction of mammalian membranes consists of glycerophospholipids, sphingolipids, and cholesterol 4 . We previously reported that a porcine liver decomposition product (PLDP) induces a significant increase in the Hasegawa's Dementia Scale-Revised (HDS-R) score in a randomized, double-blind, placebo-controlled study in healthy hu...

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Section: Discussionsupporting

confidence: 67%

Porcine liver decomposition product-derived lysophospholipids promote microglial activation in vitro

Tsukahara

Haniu

Uemura

et al. 2020

Sci Rep

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“…Even more remarkably, the lifespan of a Harpegnathos individual is dramatically affected by changes in its social status, as the workergamergate transition results in a 5-fold increase in lifespan 24 . Given the importance of glia in protecting brains from the insults of time and disease [104][105][106][107] , we hypothesized that an expanded population of ensheathing glia in gamergates might contribute to their longer life expectancy and that the accelerated aging trajectory of workers might be accompanied by a change in the opposite direction.…”

Section: Gamergates Are Resistant To Aging-associated Decline In Enshmentioning

confidence: 99%

Social reprogramming in ants induces longevity-associated glia remodeling

Sheng

Shields

Gospočić

et al. 2019

Preprint

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Healthy brain aging is of crucial societal importance; however, the mechanisms that regulate it are largely unknown. Social insects are an outstanding model to study the impact of environment and epigenetics on brain function and aging because workers and queens arise from the same genome but display profound differences in behavior and longevity. In Harpegnathos saltator ants, adult workers can transition to a queen-like phenotypic state called gamergate. This caste transition results in reprogramming of social behavior and lifespan extension. Whether these changes in brain function and physiology cause brain remodeling at the cellular level is not known.Using single-cell RNA-sequencing of Harpegnathos brains undergoing caste transition, we uncovered shifts in neuronal and glial populations. In particular, the conversion of workers into long-lived gamergates caused the expansion of ensheathing glia, which maintain brain health by phagocytosing damaged neuronal structures. These glia cells were lost during aging in normal workers but not in longer-lived gamergates. We observed similar caste-and age-associated differences in ensheathing glia in other Hymenoptera as well as Drosophila melanogaster. We propose that enhanced glia-based neuroprotection promotes healthy brain aging and contributes to the extended lifespan of the reproductive caste in social insects.

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“…Notably, the inability to properly dispose of danger/damage-associated molecular patterns (DAMPs) such as protein aggregates, necrotic cells, and cellular debris has been shown to be a pivotal driver of both persistent and maladaptive immune activation in numerous neurological disorders [14,15]. In the case of CNS injury, inefficient removal of DAMPs has been proposed to perpetuate neuroinflammation and incite secondary CNS pathology and neurological complications [9,14,16,17]. However, we currently lack complete knowledge of the drainage pathways that the brain relies on to dispose of DAMPs and resolve tissue damage following TBI.…”

mentioning

confidence: 99%

Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis

Bolte

Hurt

Smirnov

et al. 2019

Preprint

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Traumatic brain injury (TBI) has emerged as a leading cause of death and disability. Despite being a growing medical issue, the biological factors that promote central nervous system (CNS) pathology and neurological dysfunction following TBI remain poorly characterized. Recently, the meningeal lymphatic system was identified as a critical mediator of drainage from the CNS. In comparison to other peripheral organs, our understanding of how defects in lymphatic drainage from the CNS contribute to disease is limited. It is still unknown how TBI impacts meningeal lymphatic function and whether disruptions in this drainage pathway are involved in driving TBI pathogenesis. Here we demonstrate that even mild forms of brain trauma cause severe deficits in meningeal lymphatic drainage that can last out to at least two weeks post-injury. To investigate a mechanism behind impaired lymphatic function in TBI, we examined how increased intracranial pressure (ICP) influences the meningeal lymphatics, as increased ICP commonly occurs in TBI. We demonstrate that increased ICP is capable of provoking meningeal lymphatic dysfunction. Moreover, we show that pre-existing lymphatic dysfunction mediated by targeted photoablation before TBI leads to increased neuroinflammation and cognitive deficits. These findings provide new insights into both the causes and consequences of meningeal lymphatic dysfunction in TBI and suggest that therapeutics targeting the meningeal lymphatic system may offer strategies to treat TBI.

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Phagocytosis in the Brain: Homeostasis and Disease

Cited by 233 publications

References 219 publications

Porcine liver decomposition product-derived lysophospholipids promote microglial activation in vitro

Porcine liver decomposition product-derived lysophospholipids promote microglial activation in vitro

Social reprogramming in ants induces longevity-associated glia remodeling

Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis

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