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Cited by 466Neuroinflammation and Neurodegeneration MechanismsGlaucoma and retinal disordersRetinal Diseases and Treatments

The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma.

Open access
Ramirez, Ana I., de Hoz, Rosa, Salobrar-Garcia, Elena, Salazar, Juan J., Rojas, Blanca, Ajoy, Daniel, López-Cuenca, Inés, Rojas, Pilar +2 more·2017·Frontiers in Aging Neuroscience
DOI 10.3389/fnagi.2017.00214PMC PMC5498525
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Abstract

Microglia, the immunocompetent cells of the central nervous system (CNS), act as neuropathology sensors and are neuroprotective under physiological conditions. Microglia react to injury and degeneration with immune-phenotypic and morphological changes, proliferation, migration, and inflammatory cytokine production. An uncontrolled microglial response secondary to sustained CNS damage can put neuronal survival at risk due to excessive inflammation. A neuroinflammatory response is considered among the etiological factors of the major aged-related neurodegenerative diseases of the CNS, and microglial cells are key players in these neurodegenerative lesions. The retina is an extension of the brain and therefore the inflammatory response in the brain can occur in the retina. The brain and retina are affected in several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and glaucoma. AD is an age-related neurodegeneration of the CNS characterized by neuronal and synaptic loss in the cerebral cortex, resulting in cognitive deficit and dementia. The extracellular deposits of beta-amyloid (Aβ) and intraneuronal accumulations of hyperphosphorylated tau protein (pTau) are the hallmarks of this disease. These deposits are also found in the retina and optic nerve. PD is a neurodegenerative locomotor disorder with the progressive loss of dopaminergic neurons in the substantia nigra. This is accompanied by Lewy body inclusion composed of α-synuclein (α-syn) aggregates. PD also involves retinal dopaminergic cell degeneration. Glaucoma is a multifactorial neurodegenerative disease of the optic nerve, characterized by retinal ganglion cell loss. In this pathology, deposition of Aβ, synuclein, and pTau has also been detected in retina. These neurodegenerative diseases share a common pathogenic mechanism, the neuroinflammation, in which microglia play an important role. Microglial activation has been reported in AD, PD, and glaucoma in relation to protein aggregates and degenerated neurons. The activated microglia can release pro-inflammatory cytokines which can aggravate and propagate neuroinflammation, thereby degenerating neurons and impairing brain as well as retinal function. The aim of the present review is to describe the contribution in retina to microglial-mediated neuroinflammation in AD, PD, and glaucomatous neurodegeneration.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that microglial-mediated neuroinflammation is a shared pathogenic mechanism in Alzheimer’s disease, Parkinson’s disease, and glaucoma, and that retinal microglial changes may mirror brain pathology. It proposes that modulating microglial phenotype, rather than simply blocking activation, could be a therapeutic strategy and that retinal imaging may aid early diagnosis and monitoring.

Key findings

  • AD, PD, and glaucoma share chronic, age-related neurodegeneration with protein aggregates, glial activation, and neuroinflammation; microglial activation has been reported in all three, including in retina.
  • Microglia can adopt neurotoxic M1-like or neuroprotective M2-like phenotypes; the review concludes that shifting M1 toward M2 may be more effective than completely blocking microglial activation.
  • In AD models, retinal Aβ plaques appeared in APPswe/PS1ΔE9 mice as early as 2.5 months, preceding brain detection; in PD patients, macular inner retinal layer thinning of 15–20% has been reported.
  • In glaucoma, microglial activation is described as one of the first events, preceding RGC loss; minocycline or high-dose irradiation reduced microglial activation and RGC death in experimental models.

Methods

  • Narrative review of literature on microglia and retinal neurodegeneration in AD, PD, and glaucoma.
  • Synthesizes human postmortem/clinical findings and animal models, including transgenic AD mice, MPTP/rotenone PD models, and experimental/DBA/2J glaucoma models.
  • Includes a summary table (Table 1) of retinal changes and a schematic figure (Figure 1) of hypothetical neuroinflammatory events; no systematic search or meta-analysis is described.

Limitations

  • The paper states that the role of microglia in glaucoma pathophysiology is poorly understood and that better knowledge is needed.
  • The paper notes contradictory evidence: Williams et al. found no evidence of Tau, Aβ, TDP-43, ubiquitin, or α-syn deposits in any part of the eyeball in AD patients.
  • Evident from the text: this is a narrative review without stated systematic search, quality appraisal, or primary data, and it relies heavily on animal models and postmortem human tissue.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fnagi.2017.00214

Cites

297 of 297 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

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  • Premisenone given

    In glaucoma, deposition of Aβ, synuclein, and pTau has been detected in retina.

    “In this pathology, deposition of Aβ, synuclein, and pTau has also been detected in retina.”
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  • Premisenone given

    Microglial activation has been reported in AD, PD, and glaucoma in relation to protein aggregates and degenerated neurons.

    “Microglial activation has been reported in AD, PD, and glaucoma in relation to protein aggregates and degenerated neurons.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    There is dendritic atrophy of the lateral geniculate nucleus in glaucoma.

    “In addition, there is a dendritic atrophy of the lateral geniculate nucleus, the site to which the RGC axons project (Gupta et al., 2007; Park and Ou, 2013).”
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    • cites Park and Ou, 2013

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    Microglial cells are key players in neurodegenerative lesions.

    “A neuroinflammatory response is considered among the etiological factors of the major aged-related neurodegenerative diseases of the CNS, and microglial cells are key players in these neurodegenerative lesions.”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    An uncontrolled microglial response secondary to sustained CNS damage can put neuronal survival at risk due to excessive inflammation.

    “An uncontrolled microglial response secondary to sustained CNS damage can put neuronal survival at risk due to excessive inflammation.”
    Quote in the paperSubstantial claim
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    Premisenone given

    The brain and retina are affected in several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and glaucoma.

    “The brain and retina are affected in several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and glaucoma.”
    Quote in the paperSubstantial claim

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    Premisecitation

    AD, PD, and glaucoma have similar mechanisms of cell injury and deposition of protein aggregates in specific anatomical areas.

    “they have similar mechanisms of cell injury and deposition of protein aggregates in specific anatomical areas (Wostyn et al., 2010; Kaarniranta et al., 2011; Ghiso et al., 2013)”
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    • cites Wostyn et al., 2010 source

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    • cites Kaarniranta et al., 2011 source

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    Interpretationreasoning

    AD, PD, and glaucoma share a common pathogenic mechanism, neuroinflammation, in which microglia play an important role.

    “These neurodegenerative diseases share a common pathogenic mechanism, the neuroinflammation, in which microglia play an important role.”
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    AD is frequently associated with vascular dysfunctions and inflammation.

    “In addition, AD is frequently associated with vascular dysfunctions and inflammation (Dudvarski Stankovic et al., 2016).”
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    Loss of neurons in PD is accompanied by abnormal intracytoplasmic filamentous aggregates called Lewy bodies.

    “The loss of neurons is accompanied by abnormal intracytoplasmic filamentous aggregates called Lewy bodies.”
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    Premisecitation

    Lewy bodies are constituted by α-syn, parkin, phosphorylated neurofilament and components of the protheosomic-ubiquitin pathway.

    “These aggregates (deposited in somas and axons) are constituted by α-syn, parkin, phosphorylated neurofilament and components of the protheosomic-ubiquitin pathway (Orr et al., 2002).”
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    • cites Orr et al., 2002 source

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    Premisecitation

    AD, PD, and glaucoma are slow and chronic neurodegenerative disorders with a strong age-related incidence.

    “they are slow and chronic neurodegenerative disorders with a strong age-related incidence”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Microglia are immunocompetent cells of the central nervous system that act as neuropathology sensors and are neuroprotective under physiological conditions.

    “Microglia, the immunocompetent cells of the central nervous system (CNS), act as neuropathology sensors and are neuroprotective under physiological conditions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The major pathology related to AD is extracellular deposit of Aβ in the form of parenchymal plaques and cerebral amyloid angiopathy co-existing with intraneuronal accumulations of hyperphosphorylated tau (neurofibrillary tangles).

    “The major pathology related to AD is the extracellular deposit of β-amyloid (Aβ) in the form of parenchymal plaques and cerebral amyloid angiopathy co-existing with intraneuronal accumulations of hyperphosphorylated tau (pTau) (neurofribillary tangles) (Ghiso et al., 2013).”
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    Premisecitation

    AD has been related to genetic mutations, including in the gene encoding the Aβ precursor protein peptide, mutations in presenilins genes, and presence of the APOE ε4 allele.

    “AD has been related to genetic mutations, among them in the gene encoding the Aβ precursor protein peptide, mutations in the presenilins genes (Calabrese et al., 2001) and the presence of the APOE ε4 allele (Martínez-Lazcano et al., 2010).”
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    Premisecitation

    Genetic factors for PD include mutations in α-syn, while mitochondrial dysfunction and oxidative stress may also act by causing the accumulation of misfolded proteins.

    “Genetic factors include mutations in α-syn (Olanow and Tatton, 1999; Pérez and Arancibia, 2007), while mitochondrial dysfunction and oxidative stress may also act by causing the accumulation of misfolded proteins (Dauer and Przedborski, 2003).”
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    • cites Olanow and Tatton, 1999

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    • cites Pérez and Arancibia, 2007

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    • cites Dauer and Przedborski, 2003 source

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    Premisecitation

    Neurodegeneration in PD could be due to exposure to dopaminergic neurotoxins such as herbicides (MPTP), insecticides (Rotenone), and metals.

    “Neurodegeneration could be due to exposure to dopaminergic neurotoxins e.g., herbicides (MPTP), insecticides (Rotenone), and metals (Hernández-Montiel, 2006).”
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    • cites Hernández-Montiel, 2006

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    Premisecitation

    PD clinical symptoms are mainly motor problems, including bradykinesia, rigidity, tremors, and postural instability; PD also presents non-motor symptoms including disorganized speech and altered moods.

    “The clinical symptoms of PD are mainly motor problems, including bradykinesia, rigidity, tremors, and postural instability. In addition, PD presents non-motor symptoms including disorganized speech and altered moods (Fakhoury, 2016).”
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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    AD is an age-related neurodegeneration of the CNS characterized by neuronal and synaptic loss in the cerebral cortex, resulting in cognitive deficit and dementia.

    “AD is an age-related neurodegeneration of the CNS characterized by neuronal and synaptic loss in the cerebral cortex, resulting in cognitive deficit and dementia.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Neurodegenerative lesions have been detected in the intracranial optic nerve, lateral geniculate nucleus, and visual cortex in glaucoma, suggesting that glaucoma could be grouped as a neurodegenerative disease.

    “Recently, neurodegenerative lesions have been detected in the intracranial optic nerve, the lateral geniculate nucleus, and the visual cortex (Gupta et al., 2006, 2007), suggesting that this pathology could be grouped as a neurodegenerative disease (Yucel et al., 2003).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Gupta et al., 2006, 2007

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    • cites Yucel et al., 2003 source

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    Premisenone given

    The main etiological factors proposed for PD are aging, environmental toxins, and genetic factors.

    “The main etiological factors proposed for PD are aging, environmental toxins, and genetic factors.”
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    AD involves progressive memory loss and dementia.

    “AD involves progressive memory loss and dementia (Sharma and Lipincott, 2017)”
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    • cites Sharma and Lipincott, 2017

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    PD is a neurodegenerative locomotor disorder with progressive loss of dopaminergic neurons in the substantia nigra.

    “PD is a neurodegenerative locomotor disorder with the progressive loss of dopaminergic neurons in the substantia nigra.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Glaucoma is a multifactorial neurodegenerative disease of the optic nerve, characterized by retinal ganglion cell loss.

    “Glaucoma is a multifactorial neurodegenerative disease of the optic nerve, characterized by retinal ganglion cell loss.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Activated microglia can release pro-inflammatory cytokines which can aggravate and propagate neuroinflammation, thereby degenerating neurons and impairing brain as well as retinal function.

    “The activated microglia can release pro-inflammatory cytokines which can aggravate and propagate neuroinflammation, thereby degenerating neurons and impairing brain as well as retinal function.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PD is a chronic and progressive movement disorder.

    “while the PD is a chronic and progressive movement disorder (Orr et al., 2002).”
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    • cites Orr et al., 2002 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Extracellular deposits of beta-amyloid and intraneuronal accumulations of hyperphosphorylated tau protein are the hallmarks of AD.

    “The extracellular deposits of beta-amyloid (Aβ) and intraneuronal accumulations of hyperphosphorylated tau protein (pTau) are the hallmarks of this disease.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    AD and PD are the most common neurodegenerative disorders.

    “Alzheimer's Disease (AD) and Parkinson's Disease (PD) are the most common neurodegenerative disorders (de Lau and Breteler, 2006).”
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    • cites de Lau and Breteler, 2006 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Glaucoma is an age-related multifactorial neurodegenerative disease of the optic nerve, with an irreversible decrease in retinal ganglion cells, causing visual-field loss and cupping of the optic nerve head.

    “Glaucoma is an age-related multifactorial neurodegenerative disease of the optic nerve, with an irreversible decrease in RGCs, causing a visual-field loss and cupping of the optic nerve head (Quigley et al., 1988).”
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    • cites Quigley et al., 1988 source

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    Premisenone given

    A neuroinflammatory response is considered among the etiological factors of the major aged-related neurodegenerative diseases of the CNS.

    “A neuroinflammatory response is considered among the etiological factors of the major aged-related neurodegenerative diseases of the CNS, and microglial cells are key players in these neurodegenerative lesions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    PD is accompanied by Lewy body inclusion composed of α-synuclein aggregates.

    “This is accompanied by Lewy body inclusion composed of α-synuclein (α-syn) aggregates.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    AD has a multifactorial origin and seems to result from a complex interaction of multiple environmental and genetic factors.

    “However, it is now known to have a multifactorial origin and it seems to result from a complex interaction of multiple environmental and genetic factors (Wostyn et al., 2010).”
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    Premisenone given

    Aβ and pTau deposits are also found in the retina and optic nerve.

    “These deposits are also found in the retina and optic nerve.”
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    Premisenone given

    In glaucoma, increased intraocular pressure, vascular dysregulation, and immune system activation can trigger changes in retina and optic nerve including disrupted axonal transport and neurofilament accumulation, microvascular abnormalities, extracellular matrix remodeling, and glial cell activation.

    “In glaucoma, increased intraocular pressure (IOP), vascular dysregulation, and the immune system activation can trigger several changes in retina and optic nerve including: disrupted axonal transport and neurofilament accumulation, microvascular abnormalities, extracellular matrix remodeling, and glial cell activation.”
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    Premisenone given

    Microglia react to injury and degeneration with immune-phenotypic and morphological changes, proliferation, migration, and inflammatory cytokine production.

    “Microglia react to injury and degeneration with immune-phenotypic and morphological changes, proliferation, migration, and inflammatory cytokine production.”
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    Premisecitation

    PD is characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta and nerve terminals in the striatum.

    “PD is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the nerve terminals in the striatum (Dauer and Przedborski, 2003).”
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    • cites Dauer and Przedborski, 2003 source

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    Premisenone given

    PD involves retinal dopaminergic cell degeneration.

    “PD also involves retinal dopaminergic cell degeneration.”
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    Interpretationreasoning

    Excessive microglia activation might prompt the release of cytotoxic factors, causing neuronal damage, which could accelerate the progression of some CNS diseases.

    “Excessive microglia activation might prompt the release of cytotoxic factors, causing neuronal damage, which could accelerate the progression of some CNS diseases.”
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    Premisecitation

    M2-like microglia secrete anti-inflammatory mediators and neurotrophic factors, thus inducing a supportive microenvironment for neurons.

    “The second microglial phenotype, M2-like, secrete anti-inflammatory mediators and neurotrophic factors, thus inducing a supportive microenvironment for neurons (Kettenmann et al., 2011).”
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    • cites Kettenmann et al., 2011 source

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    Interpretationcitation

    Changes in OCT measurements have been used to study the course of AD, PD, and glaucoma, suggesting that the data compiled may be useful as a biomarker in diagnosing and treating neurodegenerative disease.

    “Changes in OCT measurements have been used to study the course of particular neurologic diseases such AD (Garcia-Martin et al., 2014; Maldonado et al., 2015; Salobrar-Garcia et al., 2015, 2016a,b), PD (Yu et al., 2014; Stemplewitz et al., 2015; Boeke et al., 2016; Satue et al., 2017), and glaucoma (Leung, 2016; Fallon et al., 2017), suggesting that the data compiled may be useful as a biomarker in”
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    • cites Yu et al., 2014

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    Premisecitation

    Fractalkine expressed by neurons can induce adenosine release from microglia; this adenosine via adenosine A1 receptor can activate survival pathways in neurons sensitive to excitotoxicity challenge.

    “The fractalkine expressed by neurons can induce adenosine release from microglia. This adenosine (via adenosine A1 receptor) can activate survival pathways in neurons sensitive to excitotoxicity challenge (Lauro et al., 2008, 2010).”
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    • cites Lauro et al., 2008, 2010

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    Premisenone given

    Microglia constitute the first line of immune defense in the CNS.

    “Microglia constitute the first line of immune defense in CNS.”
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    Premisecitation

    The retina is a "window to the brain," and the manifestation of disease in the brain is the same as in the retina.

    “Thus, it has been described that the retina is a “window to the brain,” and the manifestation of disease in the brain is the same as in the retina (MacCormick et al., 2015).”
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    • cites MacCormick et al., 2015 source

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    Premisecitation

    These microvesicles are involved in all immune activities and can be protective or detrimental, affecting some pathologies of the CNS.

    “These microvesicles are involved in all immune activities and can be protective or detrimental, affecting some pathologies of the CNS.”
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    Premisecitation

    In certain circumstances, neuroinflammation can help stimulate myelin repair or remove toxic aggregated proteins and cell debris from the CNS.

    “However, in certain circumstances, the neuroinflammation can help stimulate myelin repair or remove toxic aggregated proteins and cell debris from CNS (Ding et al., 2004; Simard et al., 2006; Glezer et al., 2007).”
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    • cites Ding et al., 2004 source

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    • cites Simard et al., 2006 source

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    • cites Glezer et al., 2007 source

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    Interpretationreasoning

    Although the exact mechanism bringing about neuronal death remains unknown, these neurodegenerative disorders seem to have pathogenic mechanisms in common.

    “Although the exact mechanism bringing about this neuronal death remains unknown, these neurodegenerative disorders seem to have pathogenic mechanisms in common.”
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    Premisecitation

    Microglia survey the CNS to detect homeostasis alteration and respond accordingly, combining a defensive service with neuroprotective functions.

    “These cells survey the CNS in order to detect homeostasis alteration and they respond accordingly, combining a defensive service with neuroprotective functions (Verkhratsky and Butt, 2013).”
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    • cites Verkhratsky and Butt, 2013

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    Premisecitation

    The change of microglia between M1 and M2 phenotypes is a dynamic process and microglial activation can switch from M2 to M1 phenotype during the course of disease.

    “The change of microglia between M1 and M2 phenotypes is a dynamic process and microglial activation can switch from M2 to M1 phenotype during the course of disease (Cherry et al., 2014).”
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    • cites Cherry et al., 2014 source

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    Premisecitation

    The morphology of activated microglia includes retraction of processes, enlargement of the soma, and increased expression of myeloid cell markers.

    “The morphology of activated microglia includes a retraction of processes, enlargement of the soma, and increased expression of myeloid cell markers (Ransohoff and Cardona, 2010).”
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    • cites Ransohoff and Cardona, 2010 source

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    Premisecitation

    After acute M1 activation, microglial cells can suffer an uncontrolled activation leading to a state of chronic inflammation; in this state, microglia release neurotoxic inflammatory factors (TNF-α, IL-1α, IL-1β, IL-6, NO, hydrogen peroxide, superoxide anion, chemokines, and glutamate), which lead to neuronal death.

    “After this acute M1 activation, microglial cells can suffer an uncontrolled activation leading to a state of chronic inflammation. In this state, microglia release neurotoxic inflammatory factors (TNF-α, IL-1α, IL-1β, IL-6, NO, hydrogen peroxide, superoxide anion, chemokines, and glutamate), which lead to neuronal death (Block et al., 2007; Lull and Block, 2010; Burguillos et al., 2011; Kettenmann”
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    • cites Block et al., 2007 source

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    Premisecitation

    M1 microglial cells present amoeboid morphology as well as high phagocytic capacity and motility.

    “M1 microglial cells present amoeboid morphology as well as high phagocytic capacity and motility (Varnum and Ikezu, 2012; Gonzalez et al., 2014; Jones and Bouvier, 2014).”
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    • cites Varnum and Ikezu, 2012

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    • cites Jones and Bouvier, 2014

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    Premisenone given

    The neuroinflammatory process occurs not only in the brain, but also in the retina, which is a projection of the CNS.

    “The neuroinflammatory process occurs not only in the brain, but also in the retina, which is a projection of the CNS.”
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    Premisenone given

    EVs have a heterogeneous molecular composition, including receptors, integrins and cytokines, bioactive lipids, miRNA, mRNA, DNA, and organelles, being similar to their parental cells.

    “EVs have a heterogeneous molecular composition, including receptors, integrins and cytokines, bioactive lipids, miRNA, mRNA, DNA, and organelles, being similar to their parental cells.”
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    Premisecitation

    M2 microglia are the major effector cells with the potential to dampen pro-inflammatory immune responses and promote the expression of repair genes.

    “M2 microglia are the major effector cells with the potential to dampen pro-inflammatory immune responses and promote the expression of repair genes (Tang and Le, 2016).”
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    • cites Tang and Le, 2016 source

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    Premisecitation

    Microglial cells are CNS resident immune cells which have sensor and effector functions as well as phagocytic capacity.

    “Microglial cells are CNS resident immune cells which have sensor and effector functions as well as phagocytic capacity (Streit et al., 2005).”
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    • cites Streit et al., 2005 source

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    Premisecitation

    The retina and brain are similar and respond similarly to disease.

    “The retina and brain are associated over a range of neurological and neurovascular conditions of varying etiologies, because the retina and brain are similar, and respond similarly to disease.”
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    Premisenone given

    Microglial cells may undergo two different kinds of activation in response to infections or injuries: M1-like and M2-like.

    “Microglial cells may undergo two different kinds of activation in response to infections or injuries. The first is a neurotoxic phenotype called M1-like.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    After injury, microglia become activated and change morphology, proliferate, migrate to damage sites, modify expression of enzymes and receptors, and release inflammatory factors such as NO, TNF-α, and IL-6.

    “After injury these cells become activated and in this state change their morphology, proliferate, migrate to the damage sites, modify the expression of enzymes and receptors, and release a variety of inflammatory factors, such as NO, tumor necrosis factor (TNF-α), interleukin (IL-6) among others (Magni et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Magni et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    M2 microglia can release anti-inflammatory cytokines including IL-4, IL-13, IL-10, TGF-β and neurotrophic factors such as IGF-1 to assist inflammation resolution and promote neuron survival.

    “These cells can release anti-inflammatory cytokines including IL-4, IL-13, IL-10, TGF-β and neurotrophic factors, such as insulin-like growth factor 1 (IGF-1) to assist inflammation resolution and promote neuron survival (Suh et al., 2013; Tang and Le, 2016).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Suh et al., 2013 source

      Not checked in the free run.

    • cites Tang and Le, 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Neuroinflammation is essential to protect CNS tissue, but uncontrolled and prolonged neuroinflammation is potentially harmful and can cause cellular damage.

    “Neuroinflammation, the inflammation of central nervous system (CNS), is essential to protect the tissue. However, uncontrolled and prolonged neuroinflammation is potentially harmful and can cause cellular damage.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Fractalkine is released by neurons and its receptor is expressed by microglia, constituting a neuron-microglial signaling system.

    “Fractalkine, involved in indirect neuroprotection, is released by neurons and the receptor is expressed by microglia, their interactions constituting a neuron-microglial signaling system (Ransohoff and El Khoury, 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ransohoff and El Khoury, 2015 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Microglia express CD11b/c, D45low, and the chemokine fractalkine receptor (CX3CR1).

    “Microglia express CD11b/c, D45low, and the chemokine fractalkine receptor (CX3CR1) (Dudvarski Stankovic et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dudvarski Stankovic et al., 2016 source

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  • May combine two claims.

    Interpretationcitation

    Microglial EVs represent a "liquid biopsy" of their parental cells, and could provide information on the functional phenotype (protective or damaging) of microglial cells over the course of neurodegeneration.

    “The microglial EVs representing a “liquid biopsy” of their parental cells, and could provide information on the functional phenotype (protective or damaging) of microglial cells over the course of neurodegeneration (Nigro et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nigro et al., 2016 source

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  • May combine two claims.

    Premisenone given

    After injury, astrocytes produce cytokines and chemokines (CCL2, CXCL1, CXCL10, GM-CSF, and IL-6), which activate microglia and recruit peripheral immune cells to the CNS.

    “After injury, astrocytes produce cytokines and chemokines (CCL2, CXCL1, CXCL10, GM-CSF, and IL-6), which activate microglia and recruit peripheral immune cells to the CNS.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Microglia and astrocytes are the main innate immune effector cells in the CNS.

    “Microglia and astrocytes are the main innate immune effector cells in the CNS (da Fonseca et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites da Fonseca et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In AD, PD, and glaucoma, death occurs in one or more populations of neurons (retinal ganglion cells in glaucoma, hippocampal and cortical neurons in AD, and nigrostriatal dopaminergic neurons in PD).

    “death occurs in one or more populations of neurons (RGCs in glaucoma, hippocampal and cortical neurons in AD and nigrostriatal dopaminergic neurons in PD) (Mattson, 2000).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mattson, 2000 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In their state of high activation, microglial cells acquire an amoeboid morphology and act like macrophages, engulfing debris.

    “In their state of high activation, microglial cells acquire an amoeboid morphology and act like macrophages, engulfing debris (Brown and Neher, 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Brown and Neher, 2014 source

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  • May combine two claims.

    Interpretationreasoning

    All this could generate oxidative stress, which leads to neuronal death.

    “All this could generate oxidative stress, which leads to neuronal death.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Microglia, together with endothelial cells, pericytes, and astrocytes, form the functional blood-brain barrier (BBB) that selectively separates the brain parenchyma from blood circulation.

    “Microglia, together with endothelial cells, pericytes, and astrocytes, form the functional blood-brain barrier (BBB) that selectively separates the brain parenchyma from blood circulation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    NLRP3 inflammasome assembly and activation regulates activation of caspase-1, which catalyzes cleavage and activation of proinflammatory cytokines of the IL-1β family, promoting secretion of biologically active cytokines; these cytokines could induce neuronal degeneration.

    “Their assembly and activation regulates activation of caspase-1, which catalyzes the cleavage and activation of proinflammatory cytokines of the IL-1β family, promoting the secretion of these, now biologically active, cytokines. These cytokines could induce neuronal degeneration (Gold and El Khoury, 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Gold and El Khoury, 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activated microglia can induce dysfunction of the BBB, being correlated with disruption of the BBB in neurodegenerative diseases.

    “The activated microglia can induce the dysfunction of the BBB, being correlated with the disruption of the BBB in the neurodegenerative diseases (Dudvarski Stankovic et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dudvarski Stankovic et al., 2016 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    This pathway plays a critical role in the initiation and regulation of innate immune responses and adaptive immunity.

    “This pathway plays a critical role in the initiation and regulation of innate immune responses and adaptive immunity (Yan et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yan et al., 2016 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The amyloid hypothesis for AD postulates that initial deposition of Aβ triggers mechanisms that progressively lead to Tau pathology, synaptic dysfunction, inflammation, neuronal loss and finally dementia.

    “This model postulates that the initial deposition of Aβ triggers mechanisms that progressively lead to Tau pathology, synaptic dysfunction, inflammation, neuronal loss and finally to dementia (De Strooper and Karran, 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites De Strooper and Karran, 2016 source

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  • May combine two claims.

    Premisecitation

    For phagocytosis to occur, the expression of specific receptors on the microglial surface is necessary; the principal receptors are TLRs, which have high affinity for pathogens, and TREM2, which recognizes apoptotic cellular substances.

    “As mentioned above, for phagocytosis to occur the expression of specific receptors on the microglial surface is necessary. The principal receptors are the TLRs, which have high affinity for pathogens, and TREM2, which recognizes apoptotic cellular substances (Hsieh et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hsieh et al., 2009 source

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  • May combine two claims.

    Premisecitation

    The complement participates in the physiological process termed synaptic pruning; synapses and axons have to be labeled by complement components C1q and C3 before being phagocytosed, which prompts their selective recognition by microglial cells.

    “The complement also participates in the physiological process, termed synaptic pruning. The synapses and axons have to be labeled by complement components C1q and C3 before being phagocytosed, which prompts their selective recognition by microglial cells (Paolicelli et al., 2011; Linnartz et al., 2012; Schafer et al., 2012).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Paolicelli et al., 2011 source

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    • cites Linnartz et al., 2012 source

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    • cites Schafer et al., 2012 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    This pathway constitutes a pattern-recognition system by which microglial cells respond to foreign antigens and inflammation in the CNS.

    “This pathway constitutes a pattern-recognition system by which microglial cells respond to foreign antigens and inflammation in the CNS (Hanisch and Kettenmann, 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hanisch and Kettenmann, 2007 source

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  • May combine two claims.

    Premisecitation

    RAGE is an important cell-surface receptor for Aβ in endothelial cells, neurons, and microglia, and increased expression in these cell types has been demonstrated in AD.

    “The RAGE is an important cell-surface receptor for Aβ in the endothelial cells, neurons, and microglia, and increased expression in these cell types has been demonstrated in AD (Yan et al., 1996).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yan et al., 1996 source

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  • May combine two claims.

    Premisecitation

    Activated microglia can induce A1 astrocytes by secreting IL-1α, TNF, and C1q, and this type of astrocyte contributes to the death of neurons in neurodegenerative disorders and could be analog to the M1-like phenotype microglia.

    “Activated microglia can induce A1 astrocytes by secreting IL-1α, TNF, and C1q, and this type of astrocyte contribute to the death of neurons in the neurodegenerative disorders and could be analog to the M1-like phenotype microglia (Liddelow et al., 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Liddelow et al., 2017 source

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  • May combine two claims.

    Premisecitation

    This inflammation not only occurs in response to Aβ deposition, but is also capable of generating, via feedback mechanisms, more Aβ while weakening the mechanisms responsible for its elimination.

    “This inflammation not only occurs in response to Aβ deposition, but is also capable of generating, via feedback mechanisms, more Aβ while weakening the mechanisms responsible for its elimination (Parpura et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Parpura et al., 2012 source

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  • May combine two claims.

    Premisecitation

    The primary pathogenic process in AD is the accumulation of Aβ protein, which aggregates into extracellular amyloid plaques, the hallmark of this pathology.

    “The primary pathogenic process in AD is the accumulation of Aβ protein. This protein aggregates into extracellular amyloid plaques, which are the hallmark of this pathology (Southam et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Southam et al., 2016 source

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  • May combine two claims.

    Premisecitation

    TREM2 is a critical regulator of microglia and macrophage phenotype and is involved in neurodegenerative diseases.

    “This receptor is a critical regulator of microglia and macrophage phenotype and is involved in neurodegenerative diseases (Andreasson et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Andreasson et al., 2016 source

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  • May combine two claims.

    Premisecitation

    The interaction of Aβ with RAGE causes oxidative stress in neurons, enhances inflammatory responses in microglia, and is involved in reversed transport of Aβ across the BBB in endothelial cells.

    “The interaction of Aβ with RAGE causes oxidative stress in neurons, enhances inflammatory responses in microglia, and is involved in reversed transport of Aβ across the BBB in endothelial cells (Deane et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Deane et al., 2012 source

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  • May combine two claims.

    Premisecitation

    The TREM2 pathway is induced in microglial cells by anti-inflammatory cytokines, is modulated by CD33, and is down-regulated by agonists of TLR2, 4, and 9, as well as by inflammatory stimuli such as lipopolysaccharides and RNA interference; overexpression of TREM2 promotes phagocytosis and reduces the pro-inflammatory response.

    “This pathway, induced in the microglial cells by anti-inflammatory cytokines, is modulated by CD33 and is down-regulated by agonists of TLR2, 4, and 9, as well as by inflammatory stimuli such as lipopolysaccharides and RNA interference. An overexpression of TREM2 promotes phagocytosis and reduces the pro-inflammatory response (Han et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Han et al., 2017 source

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  • May combine two claims.

    Premisecitation

    The signaling pathway TREM2 regulates apoptosis, the immune response, and phagocytic activity.

    “The signaling pathway TREM2 regulates apoptosis, the immune response, and phagocytic activity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    These activated cells can release both pro- and anti-inflammatory mediators, leading to a state of chronic inflammation in the tissue.

    “These activated cells can release both pro- and anti-inflammatory mediators, leading to a state of chronic inflammation in the tissue.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Although microglia are the main agents responsible for phagocytosis of cell debris in the CNS, the complement system can play a primordial role in removing damaged and apoptotic cells.

    “Although microglia are the main agents responsible for phagocytosis of cell debris in the CNS, the complement system can play a primordial role in removing damaged and apoptotic cells (Fakhoury, 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fakhoury, 2016 source

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  • May combine two claims.

    Premisecitation

    NLRP3 inflammasome activation reduces phagocytosis of Aβ by microglial cells, thus increasing Aβ depositions and contributing to the pathogenesis of AD.

    “In addition, NLRP3 inflammasome activation reduces phagocytosis of Aβ by microglial cells, thus increasing the Aβ depositions and contributing to the pathogenesis of AD (Garlanda et al., 2013; Gold and El Khoury, 2015).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Garlanda et al., 2013 source

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    • cites Gold and El Khoury, 2015 source

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  • May combine two claims.

    Premisecitation

    After acute inflammatory damage, brain glial cells respond to repair the tissue; if the stimulus persists, it produces an inflammatory chronic state that leads to neuronal dysfunction, injury, and loss.

    “After acute inflammatory damage, the brain glial cells respond to repair the tissue. If the stimulus persists, it produces an inflammatory chronic state that leads to neuronal dysfunction, injury, and loss (Streit et al., 2004; Calsolaro and Edison, 2016).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Streit et al., 2004 source

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    • cites Calsolaro and Edison, 2016 source

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  • May combine two claims.

    Premisenone given

    After damage, microglia transform into active phagocytes; they migrate to the damaged area, adopt an amoeboid morphology, release both pro- and anti-inflammatory molecules, and remove apoptotic cells and debris.

    “After damage, microglia transform into active phagocytes. These cells migrate to the damaged area and adopt an amoeboid morphology, releasing both pro- and anti-inflammatory molecules. They also have the capacity to remove apoptotic cells and debris.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Microglial cells can activate the complement by local secretion of the complement component from both the classical and the alternative pathway and also express C3 and C5.

    “Microglial cells can activate the complement by local secretion of the complement component from both the classical and the alternative pathway and also express C3 and C5 (Luo et al., 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Luo et al., 2011

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  • May combine two claims.

    Premisecitation

    Activated microglia are capable of upregulating CD11c, MHC I, and MHC II to act as antigen-presenting cells, which activate T cells; this activation would in turn damage the nervous system.

    “In addition, activated microglia are capable of upregulating CD11c, MHC I, and MHC II to act as antigen-presenting cells, which activate T cells. This activation would in turn damage the nervous system (Xu et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Xu et al., 2016

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Although the same JAK/STAT components are used, the gene expression in response to a specific cytokine depends on the cell type.

    “Although the same JAK/STAT components are used, the gene expression in response to a specific cytokine, depending on the cell type (van Boxel-Dezaire et al., 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites van Boxel-Dezaire et al., 2006 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cytokines bind to receptors in the microglia and activate the JAK/STAT signaling pathway.

    “Cytokines bind to receptors in the microglia and activate the JAK/STAT signaling pathway (Yan et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yan et al., 2016 source

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  • May combine two claims.

    Premisenone given

    Microglial cells are important for the normal functioning of neurons in the CNS; they provide trophic support to neurons and regulate synapses.

    “Microglial cells are important for the normal functioning of neurons in the CNS. They provide trophic support to neurons and regulate synapses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Both inflammation and reduced microglial phagocytic capacity in AD can contribute to the decline in synaptic plasticity observed in this pathology.

    “Both inflammation and reduced microglial phagocytic capacity in AD can contribute to the decline in synaptic plasticity observed in this pathology (Ritzel et al., 2015; Udeochu et al., 2016).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Ritzel et al., 2015 source

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    • cites Udeochu et al., 2016 source

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  • May combine two claims.

    Premisecitation

    Synapse loss in the hippocampus and association cortices is an early hallmark of AD and strongly correlates with cognitive impairment.

    “The synapse loss in the hippocampus and association cortices is an early hallmark of AD and strongly correlates with cognitive impairment (Hong et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hong et al., 2016 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Presumably, microglial proliferation around plaques could serve as a line of defense to limit the deposition of amyloid.

    “Presumably, microglial proliferation around plaques could serve as a line of defense to limit the deposition of amyloid.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Mitochondrial malfunction leads to reduced energy metabolism and induces neuroinflammation via NO and ROS production, ultimately entailing neurodegeneration.

    “It has been suggested that mitochondrial malfunction leads to reduced energy metabolism and induces neuroinflammation via NO and ROS production, which ultimately entails neurodegeneration (Vivekanantham et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Vivekanantham et al., 2015 source

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  • May combine two claims.

    Interpretationnone given

    During development, microglia are involved in synapse elimination and these mechanisms may be aberrantly reactivated in the aged brain, contributing to synapse loss in AD.

    “During development, microglia are involved in synapse elimination and these mechanisms may be aberrantly reactivated in the aged brain, contributing to the synapse loss in AD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Activation of the fractalkine receptor (CX3CR1) in microglial cells increases synaptic strength; deficiency in this receptor results in reduced hippocampal synaptic plasticity.

    “The activation of the fractalkine receptor (CX3CR1) in microglial cells, increases synaptic strength. However, deficiency in this receptor results in a reduced hippocampal synaptic plasticity (Rogers et al., 2011; Clark et al., 2015).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Rogers et al., 2011 source

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    • cites Clark et al., 2015 source

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  • May combine two claims.

    Premisecitation

    TREM2 inhibits pro-inflammatory cytokine production, facilitates phagocytosis and promotes cell survival; thus TREM2 dysfunction could induce loss of homeostasis in the tissue.

    “TREM2 inhibits pro-inflammatory cytokine production, facilitates phagocytosis and promotes cell survival. Thus, TREM2 dysfunction could induce the loss of the homeostasis in the tissue (Painter et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Painter et al., 2015 source

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  • May combine two claims.

    Premisecitation

    In AD patients, astrocytes in the entorhinal cortex accumulate Aβ, this accumulation being positively correlated with the extent of AD.

    “In AD patients, astrocytes in the entorhinal cortex accumulate Aβ, this accumulation being positively correlated with the extent of AD (Nagele et al., 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nagele et al., 2003 source

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  • May combine two claims.

    Premisecitation

    In rat PD models, deficiency of CX3CL1 or CX3CR1 and dysfunction of CD200-CD200R signaling increase microglial activation and degeneration of DA neurons.

    “In rat PD models, both deficiency CX3CL1 or CX3CR1 as well as the dysfunction of CD200-CD200R signaling have been shown to increase microglial activation and the degeneration of DA neurons (Wang et al., 2011; Zhang et al., 2011).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Wang et al., 2011 source

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    • cites Zhang et al., 2011 source

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  • May combine two claims.

    Premisecitation

    Astrocytes can induce microglia to perform Aβ phagocytosis by regulating the release of apo E and the ATP-binding cassette (ABCA) protein; in vitro studies have demonstrated that microglial phagocytosis of Aβ is more effective in the presence of supernatants derived from astrocytes.

    “Moreover, astrocytes can also induce microglia to perform Aβ phagocytosis by regulating the release of the apo E and the ATP-binding cassette (ABCA) protein. Studies in vitro have demonstrated that microglial phagocytosis of Aβ is more effective in the presence of supernatants derived from astrocytes (Terwel et al., 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Terwel et al., 2011 source

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  • May combine two claims.

    Premisecitation

    The release of BDNF by microglial cells induces synaptic pruning; depletion of this factor in microglia results in learning and memory impairment.

    “The release of brain-derived neurotrophic factor (BDNF) by microglial cells induces synaptic pruning. However, the depletion of this factor in the microglia results in learning and memory impairment (Parkhurst et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Parkhurst et al., 2013 source

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  • May combine two claims.

    Premisecitation

    Activated microglia can shed MVs in response to several signals, including cytokines; these MVs contain bioactive molecules (IL-1β, proteases, and MHC-II) which modulate the activity of neuronal and non-neuronal cells.

    “Activated microglia can shed MVs in response to several signals, including cytokines. These MVs contain bioactive molecules (i.e., IL-1β, proteases, and MHC-II) which modulate the activity of neuronal and non-neuronal cells (Antonucci et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Antonucci et al., 2012 source

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  • May combine two claims.

    Premisecitation

    Microglial-specific genetic alterations may be related to microglial dysfunction; expression of beclin 1 is reduced in the brain of patients with AD, leading to disruption in phagocytosis and retromer-mediated recycling of the phagocytic receptors CD36 and TREM2 in microglia.

    “In addition, microglial-specific genetic alterations may be related to this microglial dysfunction. The expression of beclin 1, a protein associated with autophagy pathway, is reduced in the brain of patients with AD, leading to disruption in phagocytosis and retromer-mediated recycling of the phagocytic receptors CD36 and TREM2 in microglia (Mosher and Wyss-Coray, 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mosher and Wyss-Coray, 2014 source

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  • May combine two claims.

    Premisecitation

    Aged microglia show reduced phagocytic capacity, which could be due partly to a reduction in the ability of microglia to recognize phagocytic targets.

    “In addition, aged microglia show reduced phagocytic capacity. This process could be due partly to a reduction in the ability of microglia to recognize phagocytic targets (Udeochu et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Udeochu et al., 2016 source

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  • May combine two claims.

    Premisecitation

    In AD brains, reactive microglia have been found colocalized with amyloid plaques; reactive astrocytes accumulate around senile plaques next to activated microglia.

    “In AD brains reactive microglia has been found colocalized with amyloid plaques. In addition, the reactive astrocytes accumulate around senile plaques next to the activated microglia (Heneka et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Heneka et al., 2015 source

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  • May combine two claims.

    Premisecitation

    In the healthy adult brain, complement components are downregulated; however, in aging brains, C1q and C3 are highly upregulated and deposited on synapses, particularly in the hippocampus, the most vulnerable region in synapse loss in AD.

    “In the healthy adult brain, these complement components are downregulated. However, in aging brains, C1q and C3 are highly upregulated and are deposited on synapses, particularly in the hippocampus, the most vulnerable region in the synapse loss in AD (Bialas and Stevens, 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Bialas and Stevens, 2013 source

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  • May combine two claims.

    Premisecitation

    pTau is observed from OPL to GCL in the retina of AD patients, and from ONL to GCL in transgenic mouse.

    “In addition to Aβ plaques, pTau was observed from OPL to GCL in the retina of AD patients. Also, pTau has been found from the ONL to GCL in the transgenic mouse (Liu et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Liu et al., 2009 source

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  • May combine two claims.

    Premisecitation

    Aβ deposition in AD retina is observed from ONL to NFL, more abundant in superior region where greater neuronal degeneration is detected.

    “Aβ deposition was observed from the outer nuclear layer (ONL) to nerve fiber layer (NFL), being more abundant in the superior region of the retina where greater neuronal degeneration has been detected (Hardy and Selkoe, 2002; Selkoe, 2004, 2008; Alexandrov et al., 2011; Ratnayaka et al., 2015; Hart et al., 2016; Table 1).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Hardy and Selkoe, 2002 source

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    • cites Selkoe, 2004 source

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    • cites Alexandrov et al., 2011 source

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  • May combine two claims.

    Premisecitation

    Aβ42 presents higher cellular toxicity, more aggregation capacity, and a more direct relation with AD pathology.

    “This alloform presents higher cellular toxicity, more aggregation capacity, and a more direct relation with AD pathology (Qiu et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Qiu et al., 2015 source

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  • May combine two claims.

    Premisecitation

    AD is associated with reduction in number of optic nerve head axons and decrease in thickness of peripapillary and macular RNFL.

    “Among them, there is a reduction in the number of optic nerve head axons and a decrease in the thickness of the peripapillary and macular retinal nerve fiber layer (RNFL) (Tsai et al., 1991; Hedges et al., 1996; Danesh-Meyer et al., 2006; Iseri et al., 2006; Paquet et al., 2007; Garcia-Martin et al., 2014; Salobrar-Garcia et al., 2015; Salobrar-García et al., 2016c) (Table 1).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Tsai et al., 1991 source

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    • cites Hedges et al., 1996 source

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    • cites Danesh-Meyer et al., 2006 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Neuroinflammation is produced by integrated responses of all CNS immune cells including microglia, astrocytes, and infiltrating T-lymphocytes.

    “Neuroinflammation is produced by the set of integrated responses of all the CNS immune cells including microglia, astrocytes and infiltrating T-lymphocytes (Le et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Le et al., 2016

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Quinolinic acid released by microglia can activate NMDA receptor signaling, leading to excitotoxicity and increased inflammatory response.

    “By contrast, quinolinic acid, released by microglia, can activate the NMDA receptor-signaling pathway, leading to excitotoxicity and increasing the inflammatory response.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lim C. K. et al., 2017 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In PD patients, pKr-2 expression is significantly increased and co-localized in activated microglia in the substantia nigra, leading to disruption of nigrostriatal DA projection.

    “In addition, in PD patient's pKr-2 expression is significantly increased and co-localized in activated microglial in the substantia nigra, leading to disruption of the nigrostriatal DA projection.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Leem et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High cytosolic concentrations of free DA can produce oxidative stress and interact with α-syn, promoting neurodegeneration.

    “The high cytosolic concentrations of free DA can produce oxidative stress and can interact with α-syn, promoting the neurodegenerative process (Mosharov et al., 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mosharov et al., 2006 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gliosis in PD is atypical: astrogliosis is largely absent while microglia is highly activated.

    “Gliosis in the PD is an atypical activation where astrogliosis is largely absent while the microglia is highly activated by the disease.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Stefanova et al., 2001 source

      Not checked in the free run.

    • cites Orr et al., 2002 source

      Not checked in the free run.

    • cites Sofroniew and Vinters, 2010 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Serum populations of T-cell repertoires and interleukin-2 receptors are altered in glaucoma patients.

    “Moreover, serum alteration of the populations of T-cell repertoires and of interleukin-2 receptors has been detected (Yang et al., 2001a).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yang et al., 2001a

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CFH functions as a cofactor in inactivation of C3b in alternative complement pathway, and low CFH levels result in complement activation, triggering inflammation in retina and brain.

    “CFH functions as a cofactor in the inactivation of C3b in the alternative complement pathway, and thus low CFH levels result in complement activation, triggering inflammation in the retina and brain (Alexandrov et al., 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Alexandrov et al., 2011 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Follow-up of neuroinflammatory processes in the retinal tissue may be useful for the early diagnosis and monitoring of neurodegenerative diseases.

    “The follow up of neuroinflammatory processes in the retinal tissue may be useful for the early diagnosis and monitoring of neurodegenerative diseases.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Differential activation of microglia (M1 or M2 phenotypes) can produce a neurotoxic or neuroprotective environment.

    “The differential activation of microglia (M1 or M2 phenotypes) can produce a neurotoxic or neuroprotective environment, and could constitute a key in neuroinflammation regulation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    In the regulation of microglial activation, several cell types including neurons, astrocytes, and T-cells are involved.

    “In the regulation of microglial activation, several cell types including, neurons, astrocytes, and T-cells are involved.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PD is a motor disorder associated with degeneration of dopaminergic neurons in the substantia nigra.

    “As mentioned above, PD is a motor disorder associated with degeneration of dopaminergic neurons in the substantia nigra (Inzelberg et al., 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Inzelberg et al., 2004 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationreasoning

    In the search for a new strategy to control neuroinflammation, changing the M1 phenotype to the M2 phenotype might be more effective than blocking microglial activation completely.

    “In the search for a new strategy to control neuroinflammation, it might be more effective to change the M1 phenotype to the M2 phenotype than to block microglial activation completely.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Abnormalities in visual function are reported in PD patients and correlated with changes in retinal tissue.

    “Moreover, abnormalities in visual function have been reported (Bodis-Wollner, 1990; Nowacka et al., 2014) in PD patients and correlated with changes in retinal tissue (La Morgia et al., 2013; Yu et al., 2014) (Table 1).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bodis-Wollner, 1990 source

      Not checked in the free run.

    • cites Nowacka et al., 2014 source

      Not checked in the free run.

    • cites La Morgia et al., 2013 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    When the neuroinflammatory process is triggered by protein aggregates (Aß, α-syn, pTau etc.), peripheral immune cells infiltrate the CNS and prompt more activation of resident microglia, favoring neuroinflammatory processes.

    “When the neuroinflammatory process is triggered by protein aggregates (Aß, α-syn, pTau etc.), peripheral immune cells infiltrate CNS and prompt more activation on resident microglia, favoring neuroinflammatory processes.”
    Quote in the paperNot a substantial claim
123 of 123

  • The paper relies on this without support.

    LRRK2 is the most commonly mutated gene in both idiopathic and familial PD.

    “LRRK2 is the most commonly mutated gene in both idiopathic and familial PD.”

  • The paper relies on this without support.

    Persistent microglial activation exerts harmful effects that result in dopaminergic neuron death.

    “Persistent microglial activation is known to exert harmful effects that result in dopaminergic neuron death.”

  • The paper relies on this without support.

    Dopaminergic neurons are especially sensitive to factors that can induce cell damage and eventually cell death.

    “In addition, dopaminergic neurons seem to be especially sensitive to several factors that can induce cell damage and eventually cell death.”

  • The paper relies on this without support.

    Astrocytes secrete glutathione and transport it to neurons in response to neural excitatory stimuli.

    “Astrocytes are responsible for secreting glutathione and transporting to neurons in response to neural excitatory stimuli.”

  • The paper relies on this without support.

    α-syn aggregates are related to neurodegenerative disorders, including PD.

    “However, α-syn aggregates are related to neurodegenerative disorders, including PD.”

  • The paper relies on this without support.

    Under physiological conditions, some microglial cells express very low levels of MHC-II, although pro-inflammatory cytokines can upregulate MHC-II expression by microglial cells.

    “Under physiological conditions, some microglial cells express very low levels of MHC-II, although certain pro-inflammatory cytokines (e.g., TNF-α or IFN-γ) can upregulate MHC-II expression by microglial cells.”

  • The paper relies on this without support.

    For retinal homeostasis, the level of complement proteins should be low.

    “For retinal homeostasis, the level of complement proteins should be low.”

  • The paper relies on this without support.

    The retina is a projection of the CNS.

    “because the retina is a projection of the CNS.”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In early AD, microglia migrate to Aβ plaques.

    “In the early stage of AD, microglia migrate to Aβ plagues,45, 46”

    From Acoustofluidic assembly of 3D neurospheroids to model Alzheimer's disease (2020) · cites this paper as [46]

    The “AD and microglia” section (page unavailable) says Aβ deposits can attract microglia and that microglia are found around amyloid plaques, supporting movement toward plaques. It does not establish that this occurs specifically in the early stage of AD; its discussion of early retinal activation is not a finding of migration to plaques. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Microglia form a protective barrier to protect brain tissue from the neurotoxicity of Aβ plaques.

    “forming a protective barrier to protect brain tissue from the neurotoxicity of Aβ plaques”

    From Acoustofluidic assembly of 3D neurospheroids to model Alzheimer's disease (2020) · cites this paper as [46]

    The ‘AD and microglia’ section says microglia proliferating around plaques could serve as a line of defense by limiting amyloid deposition. It presents this as a possibility, however, and adds that microglia clustered around deposits may be unable to remove amyloid; it does not establish that they form a protective barrier against plaque neurotoxicity. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Dysregulated overactive microglia may contribute to prolonged inflammation and chronic disease progression.

    “Although microglia are also neuroprotective under physiological conditions (Ramirez et al., 2017), it has been proposed that dysregulated overactive microglia, those clearing oxysterol debris by way of example, may contribute to the prolonged inflammation and chronic disease progression (Gao and Hong, 2008).”

    From Microtubule-associated protein 1 light chain 3B, (LC3B) is necessary to maintain lipid-mediated homeostasis in the retinal pigment epithelium (2018) · cites this paper as Ramirez et al., 2017

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Rotenone retinal model described as mice but cited study describes rats

    Minor

    The text calls the rotenone-treated animals mice, but the title of the cited study identifies the retinal model as rats.

1 of 1

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 5

  1. Garcia-Ospina, 2003, Neuronal DNA damage correlates with a positive detection of c-Jun, nuclear factor kB, p53 and Par-4 transcription factors in Alzheimer's disease, Rev. Neurol, 36, 1004
  2. Guimaraes, 2009, Mechanisms of secondary degeneration in the central nervous system during acute neural disorders and white matter damage, Rev. Neurol., 48, 304
  3. Martínez-Lazcano, 2010, Radicales libres y estrés oxidativo en las enfermedades neurodegenerativas, Mensaje Bioquim, 34, 43
  4. Park, 2013, Neurodegeneration in Glaucoma and Alzheimer's disease, 59
  5. Salobrar-García, cular manifestations of dementia: the eye and its role in the diagnosis and monitoring, Chapter 15

Cited by

Sorted by citations

Related

Authors
Ramirez, A. I., de Hoz, R., Salobrar-Garcia, E., Salazar, J. J., Rojas, B., Ajoy, D., López-Cuenca, I., Rojas, P., Triviño, A., & Ramírez, J. M.
Affiliations
Universidad Complutense de Madrid (ES)
ORCID
Venue
Frontiers in Aging Neuroscience
Publisher
Frontiers Media SA
Published
2017-07-06
Volume
9
Pages
214-214
ISSN
1663-4365 (ISSN-L)
DOI
10.3389/fnagi.2017.00214
PMC
PMC5498525
OpenAlex
W2728593064
Semantic Scholar
d19f3f3a860a90577db4955cf34ab6d6c58a68eb
Cited by
466
References
297
Citations by year
2026: 25 · 2025: 41 · 2024: 50 · 2023: 51 · 2022: 66 · 2021: 78 · 2020: 59 · 2019: 47 · 2018: 38 · 2017: 11
FWCI
4.09
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Aging Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Library Open Repository (Universidad Complutense Madrid) (submittedVersion)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Instituto de Salud Carlos III (RD16/0008/0005)
  • Ministerio de Economía y Competitividad (SAF-2014-53779-R)
  • Ministerio de Educación, Cultura y Deporte (FPU13/01910)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Ophthalmology › Glaucoma and retinal disorders
  • Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
Keywords
microglia, retinal neurodegeneration, neuroinflammation, Alzheimer's disease, Parkinson's disease, glaucoma, amyloid-beta, tau protein, alpha-synuclein, Lewy bodies, retinal ganglion cell death, dopaminergic neurons, optic nerve, inflammatory cytokines, microglial activation

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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