Microglia in Alzheimer’s disease

In the paper

“Using these modules to probe the single-cell expression data of Keren-Shaul et al. (2017), we revealed a unique subset of microglia, distinct from the DAM cells, that expressed an interferon-related gene module and increased numerically in brains with β-amyloid pathology (Friedman et al., 2017).”

What the sources say

• Not checked yetcites Friedman et al., 2017

In the paper

“We also review the evidence that, once activated, microglia can have harmful actions in AD, such as being the source of inflammatory factors and mediating the engulfment of neuronal synapses.”

In the paper

“In this review, we consider the genetic and cell biological data indicating that microglia have protective functions that restrain the toxic accumulation of β-amyloid and prevent the development of AD.”

In the paper

“TREM2–ligand interactions are impaired by TREM2 variants that increase AD risk (Wang et al., 2015; Kober et al., 2016; Yeh et al., 2016; Song et al., 2017), implying that these AD variants are at least partial loss-of-function mutants.”

What the sources say

• Not checked yetcites Wang et al., 2015 source
• Not checked yetcites Kober et al., 2016
• Not checked yetcites Yeh et al., 2016 source

In the paper

“TREM2 functions as a cell surface receptor on microglia; via its interaction with the activating adaptor protein DAP12 (encoded by the TYROBP gene), TREM2 stimulation initiates signal transduction pathways that promote microglial chemotaxis, phagocytosis, survival, and proliferation (Takahashi et al., 2005; Hsieh et al., 2009; Kleinberger et al., 2014; Poliani et al., 2015; Wang et al., 2015, 2016”

What the sources say

• Not checked yetcites Takahashi et al., 2005 source
• Not checked yetcites Hsieh et al., 2009 source
• Not checked yetcites Kleinberger et al., 2014 source

In the paper

“TREM2 is required for microglial phagocytosis of a variety of substrates, including apoptotic neurons, bacteria, LDL and other lipoproteins, and Aβ (Takahashi et al., 2005; N’Diaye et al., 2009; Kleinberger et al., 2014; Atagi et al., 2015; Yeh et al., 2016).”

What the sources say

• Not checked yetcites Takahashi et al., 2005 source
• Not checked yetcites N’Diaye et al., 2009
• Not checked yetcites Kleinberger et al., 2014 source

In the paper

“The interaction of TREM2 with its lipoprotein ligands (LDL, APOE, and CLU) was impaired by the AD-linked mutations of TREM2 (R47H, R62H, and D87N) and completely abolished by Nasu–Hakola disease–linked mutations (Y38C and T66M; Atagi et al., 2015; Bailey et al., 2015; Yeh et al., 2016).”

What the sources say

• Not checked yetcites Atagi et al., 2015
• Not checked yetcites Bailey et al., 2015
• Not checked yetcites Yeh et al., 2016 source

In the paper

“Because R47H appears to be a loss-of-function mutation that impairs TREM2-mediated microglial activation (see the following sections), the study of TREM2 has been instrumental in establishing the view that microglia normally operate in a protective capacity against AD (Jay et al., 2017b; Ulrich et al., 2017; Yeh et al., 2017).”

In the paper

“TREM2-deficient microglia showed reduced uptake of Aβ-lipoprotein complexes in vitro (Yeh et al., 2016) and less evidence of Aβ internalization in vivo (Wang et al., 2016; Yuan et al., 2016).”

What the sources say

• Not checked yetcites Yeh et al., 2016 source
• Not checked yetcites Wang et al., 2016 source
• Not checked yetcites Yuan et al., 2016 source

In the paper

“Notably, TREM2 binds to apolipoproteins apoE and clusterin (CLU; also known as apoJ), which are themselves encoded by AD risk genes (Atagi et al., 2015; Bailey et al., 2015; Yeh et al., 2016).”

What the sources say

• Not checked yetcites Atagi et al., 2015
• Not checked yetcites Bailey et al., 2015
• Not checked yetcites Yeh et al., 2016 source

In the paper

“SHIP1 can interact with the phosphorylated ITAM of DAP12, so it may also moderate TREM2 signaling by competing with SYK and PI3K for ITAM occupancy (Peng et al., 2010).”

What the sources say

• Not checked yetcites Peng et al., 2010

In the paper

“We suggest that the TREM2–apoE axis plays a key role in the microglial clearance of a variety of extracellular and cellular detritus and thus may be generally important for minimizing bystander damage to neurons in neurodegenerative settings.”

In the paper

“The CD33 genotype–phenotype relationship nicely aligns with that of TREM2: the TREM2 R47H mutation (which increases AD risk) reduces TREM2–ligand binding and ITAM signaling and impairs phagocytosis, whereas the CD33 variant (which reduces AD risk) prevents the CD33–ligand interaction and presumably ITIM signaling and promotes phagocytosis (Bradshaw et al., 2013; Griciuc et al., 2013).”

What the sources say

• Not checked yetcites Bradshaw et al., 2013 source
• Not checked yetcites Griciuc et al., 2013 source

In the paper

“the compaction of protofibrillary Aβ into a dense core plaque, which requires apoE and is promoted by TREM2 (Bales et al., 1997b, 1999; Bien-Ly et al., 2012; Wang et al., 2016; Yuan et al., 2016), could be a protective mechanism that limits neurotoxicity of amyloid deposits once they start to build up in the aging brain.”

What the sources say

• Not checked yetcites Bales et al., 1997b, 1999
• Not checked yetcites Bien-Ly et al., 2012 source
• Not checked yetcites Wang et al., 2016 source

In the paper

“we discuss how microglia can directly mediate synapse loss (Wu et al., 2015; Spangenberg and Green, 2017) and exacerbate tau pathology (Leyns and Holtzman, 2017).”

What the sources say

• Not checked yetcites Wu et al., 2015
• Not checked yetcites Spangenberg and Green, 2017
• Not checked yetcites Leyns and Holtzman, 2017

In the paper

“Carriers of the IL1RAP polymorphism also showed reduced signal for microglial activation using a TSPO (translocator protein)-binding positron emission tomography tracer, as well as an increased rate of temporal lobe atrophy and higher likelihood of progression from mild cognitive impairment to AD.”

What the sources say

• Not checked yetcites Ramanan et al., 2015

In the paper

“Collectively, the TREM2 studies suggest several mechanisms by which microglia can protect from accumulation of toxic Aβ species and development of AD: uptake and clearance of soluble Aβ species, phagocytosis of insoluble fibrillar Aβ deposits, induction of the activated state and chemotaxis, and compaction and corralling of amyloid plaques (Fig. 2).”

In the paper

“TREM2-deficient microglia fail to congregate or proliferate around plaques, lack the typical morphological changes of microglial activation, and show increased apoptosis (Jay et al., 2015; Wang et al., 2015, 2016; Mazaheri et al., 2017).”

What the sources say

• Not checked yetcites Jay et al., 2015 source
• Not checked yetcites Wang et al., 2015 source
• Not checked yetcites Mazaheri et al., 2017

In the paper

“electron microscopy studies have detected engulfed synaptic material in the developing hippocampus (Paolicelli et al., 2011), but not in the hippocampus of adult mice undergoing synapse loss caused by prion disease (Sisková et al., 2009; Caleo et al., 2012).”

What the sources say

• Not checked yetcites Paolicelli et al., 2011 source
• Not checked yetcites Sisková et al., 2009
• Not checked yetcites Caleo et al., 2012

In the paper

“Synaptic material is observed within microglia by light microscopy, and this synapse engulfment is reduced in C3 or CR3 knockout mice (Schafer et al., 2012).”

What the sources say

• Not checked yetcites Schafer et al., 2012 source

In the paper

“INPP5D, which encodes the lipid phosphatase SHIP1, is another AD risk gene preferentially expressed in microglia.”

In the paper

“These protective “corralling” functions were more readily observed for small, early stage plaques and appeared compromised in mice lacking one or both copies of Trem2, as well as in human AD tissues from TREM2 R47H carriers (Condello et al., 2015; Wang et al., 2016; Yuan et al., 2016).”

What the sources say

• Not checked yetcites Condello et al., 2015 source
• Not checked yetcites Wang et al., 2016 source
• Not checked yetcites Yuan et al., 2016 source

In the paper

“Human microglia in aged brains or in the vicinity of tau pathology may exhibit dystrophic, fragmented morphology, further suggesting that AD develops in the context of reduced neuroprotective microglial function (Streit et al., 2004, 2009).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Streit et al., 2004, 2009

In the paper

“SHIP1 is involved in a clathrin-independent mode of receptor endocytosis (Boucrot et al., 2015) and inhibits phagocytosis in macrophages (Cox et al., 2001; Kamen et al., 2007).”

What the sources say

• Not checked yetcites Boucrot et al., 2015 source
• Not checked yetcites Cox et al., 2001
• Not checked yetcites Kamen et al., 2007

In the paper

“Studies of C1q, C4, C3, and CR3 knockout mice suggest that the mechanism of developmental synapse pruning in the retinogeniculate system involves C1q tagging of synapses, opsonization of synapses by C3b, and subsequent phagocytosis of synapses by microglia (Stevens et al., 2007; Schafer et al., 2012; Sekar et al., 2016; Fig. 3 A).”

What the sources say

• Not checked yetcites Stevens et al., 2007 source
• Not checked yetcites Schafer et al., 2012 source
• Not checked yetcites Sekar et al., 2016 source

In the paper

“Recent evidence suggests that microglia form a protective barrier around amyloid deposits, compacting amyloid fibrils into a tightly packed and potentially less toxic form, preventing the accretion of new Aβ onto existing plaques, and reducing axonal dystrophy in the nearby neuropil (Condello et al., 2015).”

What the sources say

• Not checked yetcites Condello et al., 2015 source

In the paper

“Although human genetic data argue that proper microglial function protects against AD, there is plentiful evidence that unbridled microglia activity can be harmful to neurons in neurodegenerative disease.”

In the paper

“With β-amyloid deposition, however, some microglial processes become static, showing stable association with plaques over days or weeks, with TREM2, DAP12, and phosphotyrosine concentrated in those processes adjacent to plaques (Condello et al., 2015; Yuan et al., 2016).”

What the sources say

• Not checked yetcites Condello et al., 2015 source
• Not checked yetcites Yuan et al., 2016 source

In the paper

“The microglial gene expression profile induced by amyloid pathology (see later section on transcription) was broadly dampened in TREM2-deficient mice, indicating a key role of TREM2 in the microglial reaction to Aβ pathology (Wang et al., 2015; Keren-Shaul et al., 2017).”

What the sources say

• Not checked yetcites Wang et al., 2015 source
• Not checked yetcites Keren-Shaul et al., 2017 source

In the paper

“Amyloid plaques appear a decade or two before clinical symptoms of AD, but it is tau pathology and synapse loss that correlate best with cognitive impairment during disease progression (Jack et al., 2010).”

What the sources say

• Not checked yetcites Jack et al., 2010 source

In the paper

“If this relationship between genotype and expression level holds true in microglia, then it might explain the elevated AD risk, because higher SHIP1 level would dampen microglial activation and phagocytosis.”

In the paper

“Genetic knockout of C1q or neutralizing antibodies against C1q protect against synapse loss observed in amyloid-bearing mice or induced by injected Aβ (Fonseca et al., 2004; Hong et al., 2016).”

What the sources say

• Not checked yetcites Fonseca et al., 2004
• Not checked yetcites Hong et al., 2016 source

In the paper

“The PS19 study looked at 9 mo, when neurodegeneration is extensive, and observed preservation of piriform and entorhinal cortex volume in mice lacking TREM2, whereas tau phosphorylation and aggregation were unchanged (Leyns et al., 2017).”

What the sources say

• Not checked yetcites Leyns et al., 2017

In the paper

“Treatment with CSF1R inhibitors to deplete microglia or disable their proliferation protects against synapse loss and rescues behavioral deficits in amyloidosis mouse models (Olmos-Alonso et al., 2016; Spangenberg et al., 2016).”

What the sources say

• Not checked yetcites Olmos-Alonso et al., 2016 source
• Not checked yetcites Spangenberg et al., 2016

In the paper

“Recent studies of TREM2 function in mouse models of tau pathology reported seemingly conflicting roles, with Trem2 deletion appearing neuroprotective in the PS19 model (Leyns et al., 2017) but neurotoxic in the hTau model (Bemiller et al., 2017)”

What the sources say

• Not checked yetcites Leyns et al., 2017
• Not checked yetcites Bemiller et al., 2017

In the paper

“This suggested that besides the well-known effects of apoE4 on amyloid accumulation, apoE4 may contribute to AD pathogenesis by exacerbating neuroinflammation and tau pathology.”

In the paper

“this was reportedly accompanied by increased proinflammatory cytokines, tau pathology, and functional deficits (Cho et al., 2011; Lee et al., 2014).”

What the sources say

• Not checked yetcites Cho et al., 2011
• Not checked yetcites Lee et al., 2014 source

In the paper

“Mouse models of β-amyloidosis exhibit elevated C1q levels, with increased synaptic localization of C1q even before plaques have formed (Hong et al., 2016).”

What the sources say

• Not checked yetcites Hong et al., 2016 source

In the paper

“Thus, although there are conflicting results, most published studies in amyloidosis mouse models suggest that depleting microglia and blocking complement pathway activation may have beneficial effects in AD, at least in terms of synapse and neuron loss (Fig. 3 B).”

In the paper

“C1q is expressed in the adult brain, and protein levels rise steeply with aging, especially in the hippocampus (Stephan et al., 2013).”

What the sources say

• Not checked yetcites Stephan et al., 2013 source

In the paper

“AD-associated genes include CR1 (complement receptor 1), which plays roles in phagocytosis, clearing of immune complexes, and inhibition of complement (Khera and Das, 2009; Fonseca et al., 2016), and CLU/apoJ, which reportedly can function as an inhibitor of the terminal complement complex (Murphy et al., 1989; Tschopp et al., 1993; McDonald and Nelsestuen, 1997).”

What the sources say

• Not checked yetcites Khera and Das, 2009
• Not checked yetcites Fonseca et al., 2016 source
• Not checked yetcites Murphy et al., 1989

In the paper

“Overall, the findings imply that synapse loss around plaques is dynamically regulated by microglia and can be potentially rescued by microglia depletion despite no change or possible increase in amyloid plaque size.”

In the paper

“β-Amyloid aggregates/fibrils can act as disease-associated molecular patterns and stimulate Toll-like receptors (TLRs) and the NRLP3 inflammasome (Heneka et al., 2013, 2015), resulting in microglial production of TNFα, IL-1β, and other inflammatory cytokines.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Heneka et al., 2013, 2015

In the paper

“The study in the hTau model looked at 6 mo (long before neuronal loss) and observed greater tau phosphorylation and aggregation in TREM2-deficient mice, arguing for an early protective role of TREM2 in restraining propagation of tauopathy (Bemiller et al., 2017).”

What the sources say

• Not checked yetcites Bemiller et al., 2017

In the paper

“These studies point to a disease-associated microglial (DAM) state in which expression of a “homeostatic” gene set is reduced (e.g., Cx3cr1, P2ry12, and Tmem119) and another set of “neurodegeneration” genes is highly induced (e.g., Apoe, Axl, Csf1, Clec7a, Cst7, Igf1, Itgax/CD11c, Lilrb4, Lpl, and some major histocompatibility complex class II genes).”

What the sources say

• Not checked yetcites Orre et al., 2014
• Not checked yetcites Wang et al., 2015 source
• Not checked yetcites Keren-Shaul et al., 2017 source

In the paper

“RNA-sequencing studies of human microglia isolated from non-AD brain tissue (Galatro et al., 2017; Gosselin et al., 2017) showed broad similarity with mouse microglial gene expression profiles, although there were many differences such as higher expression of the C2 and C3 complement genes in human microglia.”

What the sources say

• Not checked yetcites Galatro et al., 2017
• Not checked yetcites Gosselin et al., 2017 source

In the paper

“Notably, DAM cells increase in number with progression of amyloidosis, lie spatially close to amyloid plaque, and show evidence of Aβ uptake.”