Microglia Function in the Central Nervous System During Health and Neurodegeneration

In the paper

“TREM2 binds polyanions, particularly phospholipids and sulfatides that may be exposed in the brain during Aβ accumulation due to neuronal cell apoptosis and myelin damage (114).”

What the sources say

• Partly supported

  The Results and Discussion support TREM2 recognition of phospholipids, including phosphatidylserine exposed by damaged or apoptotic cells, and sulfatides released by damaged myelin. The Discussion suggests a possible interaction with polyanions. The supplied claim also names HDL, LDL, and ApoE, but our copy provides no support for TREM2 binding those; those additions do not appear in the printed citing sentence. (LLM, conf=0.86)

  cites [114] sourceExperimental — accuracy not yet measured
• Partly supported

  Results §2.2 states that TREM2 binds polyanionic ligands such as phospholipids and reports activation by sulfatide. The cited paper does not establish the citing sentence’s further claim that these lipids may be exposed in the brain during Aβ accumulation because of neuronal apoptosis and myelin damage; pages are unavailable in our copy. (LLM, conf=0.84)

  cites [115] 115. Song W, Hooli B, Mullin K, Jin SC, Cella M, et al. 2016. Alzheimer's disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation. Alzheimers Dement . In press. https://doi.org/10.1016/j.jalz.2016.07.004 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results report TREM2 binding to HDL and LDL particles and lipidated APOE. The cited sentence, however, attributes binding to polyanions—particularly phospholipids and sulfatides exposed during neuronal apoptosis or myelin damage—and the passages in our copy do not establish those specific ligands or that context (searched: polyanions, sulfatides, phospholipids, myelin damage). (LLM, conf=0.84)

  cites [116] sourceExperimental — accuracy not yet measured

In the paper

“A rare arginine 47 histidine (R47H) variant of TREM2 is associated with an increased risk for AD (107, 108). This variant impairs binding of TREM2 to many phospholipid ligands (114, 125).”

What the sources say

• Supported

  The Results passage reports that the rare TREM2 variant encoding R47H was significantly associated with Alzheimer’s disease, with confirmation in additional analyses. The phospholipid-binding statement has separate citations (114, 125) and is not attributed to this source. (LLM, conf=0.94)

  cites [107] source
• Supported

  The cited paper supports the first sentence’s claim: the Results (Association of Variant with Alzheimer’s Disease) identify R47H as a rare TREM2 variant associated with significantly increased Alzheimer’s disease risk. The phospholipid-binding claim appears in a separate sentence with different citations (114, 125), so it is not attributed to this source. (LLM, conf=0.93)

  cites [108] source
• Supported

  The Introduction states that the rare R47H variant is associated with increased Alzheimer’s disease risk. The Results report reduced responses to several phospholipid ligands, and the Discussion states that R47H affected binding of multiple lipid ligands. Page numbers are not provided in our copy. (LLM, conf=0.92)

  cites [114] source

In the paper

“in a mouse model of AD, complement was activated before plaque deposition and microglia were responsible for complement-mediated synaptic loss (139).”

What the sources say

• Supported

  The Abstract reports that C1q increased and associated with synapses before overt plaque deposition. It also reports that inhibiting C1q, C3, or the microglial complement receptor CR3 reduced early synapse loss, and that microglia engulfed synaptic material in a CR3-dependent process. These passages support the claim about pre-plaque complement activation and microglial mediation of complement-dependent synapse loss in AD mouse models. (LLM, conf=0.94)

  cites [139] source

In the paper

“restraining microglial activation by ablating NF-κB signaling rescued motor neurons from microglia-mediated death in vitro and extended survival of SOD1G93A mice (151).”

What the sources say

• Supported

  The Results section on in vitro microglia–motor neuron co-cultures reports that inhibiting NF-κB in SOD1-G93A microglia fully rescued motor neuron survival. The in vivo Results report reduced inflammatory microglial markers and a 20-day increase in median survival in SOD1-G93A mice with reduced microglial NF-κB signaling. The in vivo intervention reduced signaling rather than completely eliminating it. (LLM, conf=0.91)

  cites [151] source

In the paper

“In the steady state, microglia are ramified cells with multiple branches and processes, which extend from the somata and terminate with bulbous endings. These processes are in continuous motion, protruding and retracting to cover long distances and survey large areas of the brain.”

What the sources say

• Not checked yetcites [12] source
• Not checked yetcites [13] source
• Not checked yetcites [14] source

In the paper

“Larger injuries or inflammatory stimuli induce microglia to morph from a ramified to an amoeboid shape. Cell bodies enlarge while cell processes become shortened and cover more limited areas. Amoeboid morphology reflects a highly activated state associated with phagocytosis and proinflammatory function.”

In the paper

“Alterations in microglia functionality are implicated in brain development and aging, as well as in neurodegeneration.”

In the paper

“Fate-mapping studies have demonstrated that microglia originate from early myeloid progenitors in the embryonic yolk sac that migrate into the developing neural tube, where they proliferate, colonize the entire parenchyma, and subsist throughout the life span of the organism by slow division (1, 2).”

What the sources say

• Not checked yetcites [1] source
• Not checked yetcites [2] source

In the paper

“Microglia serve as brain macrophages but are distinct from other tissue macrophages owing to their unique homeostatic phenotype and tight regulation by the central nervous system (CNS) microenvironment.”

In the paper

“Microglia are resident cells of the brain that regulate brain development, maintenance of neuronal networks, and injury repair.”

In the paper

“Genetic defects in CSF1R and pharmacological blockade of CSF1R drastically reduce microglia numbers (5, 6).”

What the sources say

• Not checked yetcites [5] source
• Not checked yetcites [6] source

In the paper

“Furthermore, as the primary source of proinflammatory cytokines, microglia are pivotal mediators of neuroinflammation and can induce or modulate a broad spectrum of cellular responses.”

In the paper

“Thus, IL-34 and CSF1 are partially redundant, such that genetic defects in either IL-34 or CSF1 result in a partial reduction of microglial numbers.”

In the paper

“In addition to immune receptors, microglia express multiple receptors for neurotransmitters and neuropeptides released by neurons that promote neural-glia communications (31). These receptors allow microglia to monitor neuronal activity by guiding microglia processes toward neuronal synapses in order to influence synaptic plasticity and sculpt dendritic spine density.”

What the sources say

• Not checked yetcites [31] source

In the paper

“In models of neurodegeneration, microglia express both neurotoxic and neuroprotective factors; genes involved in oxidative phosphorylation; and lysosome, ribosome, and spliceosome factors involved in responses to misfolded proteins, stress, and neuronal death or injury (36, 42) (Figure 1).”

What the sources say

• Not checked yetcites [36] source
• Not checked yetcites [42] source

In the paper

“M1 activation is a proinflammatory and neurotoxic state typically induced by simultaneous triggering of TLR and IFN-γ signaling pathways.”

• Also stated in: § Functional States of Microglia: Beyond the M1/M2 Paradigm · plain

  “M2 activation describes the anti-inflammatory and healing activities of microglia.”

What the sources say

• Not checked yetcites [34] Appel SH, 2011, Acta Myol
• Not checked yetcites [35] source

In the paper

“Although the M1 and M2 categories have been helpful for conceptualizing microglia activities in vitro, it is increasingly accepted that the M1/M2 paradigm is inadequate to describe microglia and macrophage activation in vivo, as microglia rarely display a significant bias toward either the M1 or M2 phenotype.”

In the paper

“Recent studies of organotypic hippocampal slice cultures have shown that microglia are crucial for protection against NMDA-induced toxicity (84). ATP released by damaged neurons activates the microglia receptor P2X7, inducing secretion of TNF-α, which tempers NMDA-induced toxicity.”

What the sources say

• Not checked yetcites [84] source

In the paper

“Though helpful, some of these markers may be modulated by activation and/or expressed in other cell types outside of the CNS; therefore, they may not be suitable for unequivocally identifying or targeting tissue-resident microglia.”

In the paper

“However, aging microglia display signs of dystrophy, including reduced ramification and short, tortuous, swollen processes (58). The ability of microglia to survey the brain and respond to insults also declines with aging (59).”

What the sources say

• Not checked yetcites [58] source
• Not checked yetcites [59] source

In the paper

“Administration of DT and subsequent depletion of microglia in these mice caused a significant reduction in motor-learning-dependent glutamatergic excitatory synapses and impaired performance in multiple learning tasks. In this model, microglia-induced synaptic plasticity depended on BDNF secretion, which activated neuronal Trk, a key mediator of synaptic plasticity (Figure 2).”

What the sources say

• Not checked yetcites [77] source

In the paper

“AD is the most common form of senile dementia, characterized by lesions consisting of extracellular masses of amyloid β (Aβ) peptides and intracellular bundles of fibrillar Tau protein.”

In the paper

“Although ApoE is likely to influence AD through multiple mechanisms, an important effect is enhancement of phagocytosis of Aβ aggregates by microglia while tempering their inflammatory responses (102) (Figure 4).”

What the sources say

• Not checked yetcites [102] source

In the paper

“Lack of NLRP3, TLR, and IL-1β signaling in transgenic mouse models of AD that express human APP and presenilin 1 mutations, attenuates Aβ deposition and prevents cognitive defects (17).”

What the sources say

• Not checked yetcites [17] source

In the paper

“TREM2 is transmembrane glycoprotein expressed in myeloid cells that transmits intracellular signals through two associated transmembrane adapters, DAP12 (also known as Tyrobp) and DAP10 (Hcst) (26, 111, 112).”

What the sources say

• Not checked yetcites [26] source
• Not checked yetcites [111] source
• Not checked yetcites [112] Xing J, 2015, Res. Rep. Biochem.

In the paper

“Neurodegenerative diseases hinge not only on misfolding of endogenous proteins, but also on protein clearance. Imbalance between generation and disposal of misfolded proteins leads to irreversible autopropagation.”

In the paper

“Prion diseases are associated with activation of microglia and astrocytes, which contribute to PrPSc clearance.”

In the paper

“Microglia can alter the course of neurodegeneration by clearing misfolded proteins by phagocytosis or, conversely, by releasing inflammatory mediators that promote protein aggregation and neuron damage (Figure 3).”

In the paper

“Subsequent studies in sporadic AD revealed that a polymorphism of apolipoprotein E (ApoE), the ApoE4 allele, is strongly associated with an increased risk of AD, whereas the ApoE2 allele is associated with protection (101).”

What the sources say

• Not checked yetcites [101] source

In the paper

“chronic stimulation of microglia by Aβ may be deleterious and cause prolonged inflammation (Figure 3) (17)”

What the sources say

• Not checked yetcites [17] source

In the paper

“DAP12 recruits the protein tyrosine kinase Syk, which activates multiple downstream signaling mediators, including PLC-γ, PI-3K, and ERK (111, 112).”

What the sources say

• Not checked yetcites [111] source
• Not checked yetcites [112] Xing J, 2015, Res. Rep. Biochem.

In the paper

“TREM2 promotes proliferation (119), survival (119), and phagocytosis of apoptotic cells (120–122).”

What the sources say

• Not checked yetcites [119] source
• Not checked yetcites [120] source
• Not checked yetcites [121] source
• Not checked yetcites [122] source

In the paper

“a CD33 variant associated with an increased risk for AD is expressed at relatively high levels, increasing CD33 inhibitory effects on myeloid functions, such as internalization of the Aβ1–42 peptide (137).”

What the sources say

• Not checked yetcites [137] source

In the paper

“suggesting that TREM2 signaling helps protect against AD but can cause harm in excess.”

In the paper

“This weakening of microglial barriers around Aβ facilitates spreading and invasiveness of fibrillar amyloid at early stages of disease (130, 131) followed by later accumulation of Aβ during disease progression (114, 132).”

What the sources say

• Not checked yetcites [130] source
• Not checked yetcites [131] source
• Not checked yetcites [114] source

In the paper

“cerebrospinal fluid levels of soluble TREM2 are a potential biomarker for microglia activity in early-stage AD and correlate with neuronal injury markers (135, 136).”

What the sources say

• Not checked yetcites [135] source
• Not checked yetcites [136] source

In the paper

“Thus, microglia in ALS have a distinct gene-expression signature that does not fit the M1/M2 paradigm but reflects microglial response to protein aggregates, stress, and neuronal cell death and partially overlaps with that of other neurodegenerative diseases”

In the paper

“C9orf72 is required for the normal function of myeloid cells, and altered microglial function may contribute to neurodegeneration in carriers of C9orf72 expansion (153).”

What the sources say

• Not checked yetcites [153] source

In the paper

“LRRK2-deficient rats, in contrast, had no significant loss of neurons and reduced numbers of activated myeloid cells in the substantia nigra (160).”

What the sources say

• Not checked yetcites [160] source

In the paper

“In human, rare gain-of-function mutations of TBK1 are associated with normal tension glaucoma. These mutations may affect autophagy and phagocytic functions of microglia (157).”

What the sources say

• Not checked yetcites [157] source

In the paper

“Mice lacking the homeobox gene Hoxb8 in all cells or only in myeloid and endothelial cells spend twice as much time grooming as do their littermates, leading to hair loss and skin lesions reminiscent of a human compulsive disorder known as trichotillomania (175).”

What the sources say

• Not checked yetcites [175] source

In the paper

“Modulation of inflammation through the adenosine A2A receptor (A2AR) also prevented neuroinflammation and protected retinal ganglion cells in vitro and in vivo (174).”

What the sources say

• Not checked yetcites [174] source

In the paper

“Studies have revealed microglial activation in depressed patients, with a greater magnitude of activation in individuals who completed suicide (181–183)”

What the sources say

• Not checked yetcites [181] source
• Not checked yetcites [182] source
• Not checked yetcites [183] source

In the paper

“In a mouse model of glaucoma, the complement pathway is upregulated before retinal ganglion cell death, while induction of C1q deficiency protects from glaucoma (69).”

What the sources say

• Not checked yetcites [69] source

In the paper

“Moreover, M1 activation is not always detrimental nor is M2 activation necessarily beneficial.”

In the paper

“Cholesterol-lowering statins (195) and other metabolic drugs (196) have been reported to subdue inflammatory microglial functions and have beneficial effects on cognitive function in mouse models of AD. Moreover, the results of observational and randomized trials in humans have shown conflicting results (195).”

What the sources say

• Not checked yetcites [195] source
• Not checked yetcites [196] source

In the paper

“In models of AD, M1 functions promote removal of amyloid plaques, while M2 functions may facilitate amyloid spreading (187).”

What the sources say

• Not checked yetcites [187] source

In the paper

“Oral administration of the RXR agonist bexarotene in a mouse model of AD facilitated rapid clearance of soluble Aβ (103). The therapeutic effect was linked to the induction of increased levels of ApoE. Moreover, a recent study showed that bexarotene induces TREM2 expression in microglia (197).”

What the sources say

• Not checked yetcites [103] source
• Not checked yetcites [197] source

In the paper

“Thus, therapeutic agents that target microglia may have beneficial effects but also adverse effects.”

In the paper

“one study showed that microglial autophagy facilitates clearance of extracellular Aβ fibrils and reduces Aβ-induced NLRP3 activation (200).”

What the sources say

• Not checked yetcites [200] source

In the paper

“M1 microglia may be neurotoxic in some cases but promote axonal regeneration in others (186).”

What the sources say

• Not checked yetcites [186] source

In the paper

“Humanized antibodies that target misfolded proteins, such as Aβ, have been developed and are currently being tested in clinical trials (188, 189).”

What the sources say

• Not checked yetcites [188] source
• Not checked yetcites [189] source

In the paper

“Microglial phagocytosis can also be a double-edged sword in neurodegeneration. On one hand, it may facilitate the clearance of misfolded proteins at disease onset; on the other hand, it may facilitate the spreading of pathogenic seeds during disease progression if protein digestion is impaired, or contribute to synapse loss if too many synapses are pruned.”

In the paper

“Another recent study showed that microglial autophagy is involved in synaptic pruning and regulates behavior (201).”

What the sources say

• Not checked yetcites [201] 201. Kim HJ, Cho MH, Shim WH, Kim JK, Jeon EY, et al. 2016. Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects. Mol. Psychiatry. In press. https://doi.org/10.1038/mp.2016.103 source

In the paper

“given the role of complement in synaptic loss and the association of CR1 mutations in AD, targeting of complement components may be a valuable option for both Aβ and Tau pathologies.”

In the paper

“Since AD is associated with hypomorphic mutations of TREM2 and hypermorphic mutations of CD33, antibodies activating TREM2 or blocking CD33 might be helpful in correcting microglial dysfunction.”

In the paper

“two recent studies showed that brain-engrafted bone marrow–derived cells either do not acquire microglial functions or do so only after a long time (202, 203).”

What the sources say

• Not checked yetcites [202] source
• Not checked yetcites [203] source