Immune Signaling in Neurodegeneration

Hammond, Timothy R.; Marsh, Samuel E.; Stevens, Beth

doi:10.1016/j.immuni.2019.03.016

Cited by 266 publications

(218 citation statements)

References 287 publications

(341 reference statements)

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“…Moreover, we show that low maternal n-3 PUFA intakeinduced modification of microglia lipid composition is the main driver leading to exacerbation of spines phagocytosis in the offspring. This process is complement-dependent, a mechanism that has been repeatedly reported to be the molecular bridge of microglia phagocytosis of spines 25,49,[62][63][64][65] . Our data also reveal that n-3 PUFA deficiency alters the shaping of hippocampal neurons and spatial working memory in pups.…”

Section: Discussionmentioning

confidence: 99%

Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the developing brain

Madore

Leyrolle²,

Morel

et al. 2019

Preprint

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Omega-3 fatty acids (n-3 polyunsaturated fatty acids; n-3 PUFAs) are essential for the functional maturation of the brain. Westernization of dietary habits in both developed and developing countries is accompanied by a progressive reduction in dietary intake of n-3PUFAs. Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental diseases in epidemiological studies, but the mechanisms by which a n-3 PUFA dietary imbalance affects CNS development are poorly understood. Active microglial engulfment of synaptic elements is an important process for normal brain development and altered synapse refinement is a hallmark of several neurodevelopmental disorders. Here, we identify a molecular mechanism for detrimental effects of low maternal n-3 PUFA intake on hippocampal development. Our results show that maternal dietary n-3 PUFA deficiency increases microglial phagocytosis of synaptic elements in the developing hippocampus, through the activation of 12/15-lipoxygenase (LOX)/12-HETE signaling, which alters neuronal morphology and affects cognition in the postnatal offspring. While women of child bearing age are at higher risk of dietary n-3 PUFA deficiency, these findings provide new insights into the mechanisms linking maternal nutrition to neurodevelopmental disorders.One Sentence Summary: Low maternal omega-3 fatty acids intake impairs microgliamediated synaptic refinement via 12-HETE pathway in the developing brain.

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Section: Discussionmentioning

confidence: 99%

Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the developing brain

Madore

Leyrolle²,

Morel

et al. 2019

Preprint

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“…Such inflammatory diseases of the CNS have to be distinguished from conditions of "neuroinflammation," which for instance occur in neurodegenerative or metabolic diseases (Becher et al, 2017; Dendrou, McVean, & Fugger, 2016;Hammond, Marsh, & Stevens, 2019). In these conditions brain injury is associated by immune reactions, which are associated with tissue injury.…”

mentioning

confidence: 99%

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

Lassmann

2019

Glia

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Numerous recent studies have been performed to elucidate the function of microglia, macrophages, and astrocytes in inflammatory diseases of the central nervous system. Regarding myeloid cells a core pattern of activation has been identified, starting with the activation of resident homeostatic microglia followed by recruitment of blood borne myeloid cells. An initial state of proinflammatory activation is at later stages followed by a shift toward an‐anti‐inflammatory and repair promoting phenotype. Although this core pattern is similar between experimental models and inflammatory conditions in the human brain, there are important differences. Even in the normal human brain a preactivated microglia phenotype is evident, and there are disease specific and lesion stage specific differences in the contribution between resident and recruited myeloid cells and their lesion state specific activation profiles. Reasons for these findings reside in species related differences and in differential exposure to different environmental cues. Most importantly, however, experimental rodent studies on brain inflammation are mainly focused on autoimmune encephalomyelitis, while there is a very broad spectrum of human inflammatory diseases of the central nervous system, triggered and propagated by a variety of different immune mechanisms.

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“…However, the role of the complement 338 cascade in aging and neurodegenerative diseases has been more widely studied. Inhibition of C1QA 339 prevented synapse loss in aging mice and in mouse models of AD, Parkinson's disease, and glaucoma 340 (Hammond et al, 2019). However, although inhibition of C3 appeared protective to the aging brain, 341 deficiency of C3 exacerbated some phenotypes in mouse models of AD and glaucoma (Hammond et 342 al., 2019).…”

Section: Discussion 322mentioning

confidence: 99%

“…These findings suggest the protection mediated by C1QA deficiency may be due to 416 inhibition of complement-expressing microglial cells directly. Although circulating complement 417 components account for approximately 4% of blood proteins, in young, aging diseased brains, 418 complement components are also synthesized by multiple cell types including myeloid cells, 419 astrocytes, neurons and endothelial cells (Hammond et al, 2019). In the aging brain, microglia and 420 astrocytes are thought to be a major source of complement proteins .…”

mentioning

confidence: 99%

Deficiency of complement component C1Q prevents cerebrovascular damage and white matter loss in a mouse model of chronic obesity

Graham

Kocalis

Soto

et al. 2020

Preprint

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ABSTRACTAge-related cognitive decline and many dementias involve complex interactions of both genetic and environmental risk factors. Recent evidence has demonstrated a strong association of obesity with the development of dementia. Furthermore, white matter damage is found in obese subjects and mouse models of obesity. Here, we found that components of the complement cascade, including C1QA and C3 are increased in the brain of western diet (WD)-fed obese mice, particularly in white matter regions. To functionally test the role of the complement cascade in obesity induced brain pathology, female and male mice deficient in complement component 1qa (C1QA), an essential molecule in the activation of the classical pathway of the complement cascade, were fed a WD and compared to WD-fed WT mice, and to C1qa knockout (KO) and WT mice fed a control diet (CD). C1qa KO mice fed a WD became obese but did not show pericyte loss or a decrease in laminin density in the cortex and hippocampus that was observed in obese WT controls. Furthermore, obesity-induced microglia phagocytosis and breakdown of myelin in the corpus callosum were also prevented by deficiency of C1QA. Collectively, these data show that C1QA is necessary for damage to the cerebrovasculature and white matter damage in diet-induced obesity.SIGNIFICANCE STATEMENTEconomic growth, an increasingly sedentary lifestyle and a nutritional transition to processed foods and high calorie diets have led to a significant increase in obesity prevalence. Several chronic diseases have been associated with obesity, including dementia. Obesity-induced, peripheral inflammation has been proposed as a possible trigger of pathological changes in the brain that lead to cognitive dysfunction and predisposition to dementia. Here we show that genetic deletion of the complement component C1QA prevents cerebrovascular damage, neuroinflammation and white matter degradation in a mouse model of western diet-induced obesity, demonstrating that inflammatory responses play a significant role in obesity-induced brain pathology. The complement pathway is an attractive therapeutic target to prevent cognitive decline and reduction of dementia risk caused by obesity.

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Immune Signaling in Neurodegeneration

Cited by 266 publications

References 287 publications

Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the developing brain

Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the developing brain

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

Deficiency of complement component C1Q prevents cerebrovascular damage and white matter loss in a mouse model of chronic obesity

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