CoChat
Sign Up
Cited by 231Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.

Microglia in Alzheimer’s Disease: Activated, Dysfunctional or Degenerative

Open access
Navarro, Victoria, Sanchez-Mejias, Elisabeth, Jimenez, Sebastian, Muñoz-Castro, Clara, Sanchez-Varo, Raquel, Davila, Jose C., Vizuete, Marisa, Gutierrez, Antonia, Vitorica, Javier·2018·Frontiers in Aging Neuroscience
DOI 10.3389/fnagi.2018.00140PMC PMC5958192
Open this paper in CoChat — free account

Abstract

Microglial activation has been considered a crucial player in the pathological process of multiple human neurodegenerative diseases. In some of these pathologies, such as Amyotrophic Lateral Sclerosis or Multiple Sclerosis, the immune system and microglial cells (as part of the cerebral immunity) play a central role. In other degenerative processes, such as Alzheimer's disease (AD), the role of microglia is far to be elucidated. In this "mini-review" article, we briefly highlight our recent data comparing the microglial response between amyloidogenic transgenic models, such as APP/PS1 and AD patients. Since the AD pathology could display regional heterogeneity, we focus our work at the hippocampal formation. In APP based models a prominent microglial response is triggered around amyloid-beta (Aβ) plaques. These strongly activated microglial cells could drive the AD pathology and, in consequence, could be implicated in the neurodegenerative process observed in models. On the contrary, the microglial response in human samples is, at least, partial or attenuated. This patent difference could simply reflect the lower and probably slower Aβ production observed in human hippocampal samples, in comparison with models, or could reflect the consequence of a chronic long-standing microglial activation. Beside this differential response, we also observed microglial degeneration in Braak V-VI individuals that, indeed, could compromise their normal role of surveying the brain environment and respond to the damage. This microglial degeneration, particularly relevant at the dentate gyrus, might be mediated by the accumulation of toxic soluble phospho-tau species. The consequences of this probably deficient immunological protection, observed in AD patients, are unknown.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3389/fnagi.2018.00140

Cites

53 of 53 references verified0 citation errors · 0 not checkable

Statistics

Figures

Figure 1 Microglial activation in APP/PS1 and microglial pathology in Alzheimer’s disease (AD) hippocampus. (A) Differential expression of selected microglial genes from hippocampus of 9- to 12-month-old APP/PS1 mice (age-matched wild-type (WT) as controls; n = 10 per genotype) and post-mortem human Braak V–VI samples (n = 28; age-matched non-demented BraaK II individuals as controls, n = 21) determined by qPCR analysis. Data were graphically plotted as Z-score and represented the deviation in the expression of a gene over the mean expression of this particular gene in the control populations (WT or Braak II). Each bar represented an individual murine or human sample. High expression is marked by the red color spectrum, low expression by blue colors. (B) Immunohistochemical detection of microglial cells around amyloid plaques in 12-month old APP/PS1 mice (b1,b2), human AD brains staged as Braak IV (b3,b4) or Braak V–VI (b5,b6). Amyloid plaques are surrounded by abundant activated Iba1-positive (b1) and CD45-positive (b2) microglia in the transgenic mice. Human plaques also displayed Iba1-positive and CD45-positive associated microglia at Braak IV stage, however the presence of amyloid deposits devoid of Iba1-positive microglia was often present in the hippocampus of Braak V–VI cases. Asterisks indicate amyloid plaques. BV, blood vessel. Scale bars (b1–b4) 20 μm; (b) 200 μm; (b6) 50 μm. (C,D) The Iba1-load quantitative analysis revealed a regional pattern with DG>CA3>CA1>parahippocampal gyrus (PHG) in Braak II (C,c1–4,D, green circles). In Braak V–VI individuals a significant (p < 0.05, Mann Whitney test) reduction of the microglial load was evidenced in the DG and CA3 regions (D, orange squares). (E) Compared to Braak II microglial cells (e1 shows a non-activated healthy Iba1-positive microglial cell), Braak V–VI cases exhibit microglial cells with degenerative morphological features including deramification (e2), fragmentation (e3), beadings and spheroidal swellings (e4,e5) and dystrophies (e6) of the processes. h, hilar region; g, granular layer; m, molecular layer; so, stratum oriens; sp, stratum pyramidale; sl, stratum lucidum; sr, stratum radiatum. Scale bars, (c1–8) 100 μm; (e1–6) 20 μm. (F) Differential accumulation of soluble Aβ and phospho-tau forms in the hippocampus of human Braak II and Braak V–VI brains. Quantitative data from dot blots or western blots of soluble S1 fractions (extracellular/cytosolic) isolated from Braak II (n = 8) or Braak V–VI (n = 8) individuals. The relative abundance of A11 or OC positive Abeta oligomers, AT8 or AT100 phospho-tau proteins was determined by densitometry analysis. Significance was determined by Mann Whitney test. (G) Soluble phospho-tau toxicity on BV2 microglial cells. Microglia were incubated with S1 fractions isolated from Braak II, V–VI samples or 18-month-old APP/PS1 or 12-month-old Thy1-tau22 models. The toxicity was analyzed by flow cytometry and the percent of viable cells was showed. The Aβ or phospho-tau was immunodepleted from the Braak V–VI S1 fractions using 6E10 plus 82E1 or AT8 plus AT100 antibodies, respectively. The data are shown as the mean ± SD of six different experiments. Significance (indicated in the figure) was determined by ANOVA and Tukey post hoc test. Data were taken from Jimenez et al. (2008, 2014); Moreno-Gonzalez et al. (2009); Sanchez-Mejias et al. (2016); Baglietto-Vargas et al. (2017) and Gutierrez and Vitorica (2018).
Figure 1 Microglial activation in APP/PS1 and microglial pathology in Alzheimer’s disease (AD) hippocampus. (A) Differential expression of selected microglial genes from hippocampus of 9- to 12-month-old APP/PS1 mice (age-matched wild-type (WT) as controls; n = 10 per genotype) and post-mortem human Braak V–VI samples (n = 28; age-matched non-demented BraaK II individuals as controls, n = 21) determined by qPCR analysis. Data were graphically plotted as Z-score and represented the deviation in the expression of a gene over the mean expression of this particular gene in the control populations (WT or Braak II). Each bar represented an individual murine or human sample. High expression is marked by the red color spectrum, low expression by blue colors. (B) Immunohistochemical detection of microglial cells around amyloid plaques in 12-month old APP/PS1 mice (b1,b2), human AD brains staged as Braak IV (b3,b4) or Braak V–VI (b5,b6). Amyloid plaques are surrounded by abundant activated Iba1-positive (b1) and CD45-positive (b2) microglia in the transgenic mice. Human plaques also displayed Iba1-positive and CD45-positive associated microglia at Braak IV stage, however the presence of amyloid deposits devoid of Iba1-positive microglia was often present in the hippocampus of Braak V–VI cases. Asterisks indicate amyloid plaques. BV, blood vessel. Scale bars (b1–b4) 20 μm; (b) 200 μm; (b6) 50 μm. (C,D) The Iba1-load quantitative analysis revealed a regional pattern with DG>CA3>CA1>parahippocampal gyrus (PHG) in Braak II (C,c1–4,D, green circles). In Braak V–VI individuals a significant (p < 0.05, Mann Whitney test) reduction of the microglial load was evidenced in the DG and CA3 regions (D, orange squares). (E) Compared to Braak II microglial cells (e1 shows a non-activated healthy Iba1-positive microglial cell), Braak V–VI cases exhibit microglial cells with degenerative morphological features including deramification (e2), fragmentation (e3), beadings and spheroidal swellings (e4,e5) and dystrophies (e6) of the processes. h, hilar region; g, granular layer; m, molecular layer; so, stratum oriens; sp, stratum pyramidale; sl, stratum lucidum; sr, stratum radiatum. Scale bars, (c1–8) 100 μm; (e1–6) 20 μm. (F) Differential accumulation of soluble Aβ and phospho-tau forms in the hippocampus of human Braak II and Braak V–VI brains. Quantitative data from dot blots or western blots of soluble S1 fractions (extracellular/cytosolic) isolated from Braak II (n = 8) or Braak V–VI (n = 8) individuals. The relative abundance of A11 or OC positive Abeta oligomers, AT8 or AT100 phospho-tau proteins was determined by densitometry analysis. Significance was determined by Mann Whitney test. (G) Soluble phospho-tau toxicity on BV2 microglial cells. Microglia were incubated with S1 fractions isolated from Braak II, V–VI samples or 18-month-old APP/PS1 or 12-month-old Thy1-tau22 models. The toxicity was analyzed by flow cytometry and the percent of viable cells was showed. The Aβ or phospho-tau was immunodepleted from the Braak V–VI S1 fractions using 6E10 plus 82E1 or AT8 plus AT100 antibodies, respectively. The data are shown as the mean ± SD of six different experiments. Significance (indicated in the figure) was determined by ANOVA and Tukey post hoc test. Data were taken from Jimenez et al. (2008, 2014); Moreno-Gonzalez et al. (2009); Sanchez-Mejias et al. (2016); Baglietto-Vargas et al. (2017) and Gutierrez and Vitorica (2018).CC BY · PubMed Central
Figure 2 Dissimilar progressions of hippocampal microglial response in APP/PS1 mice and human brains. (A) Illustrate the age-dependent microglial activation in the amyloidogenic model from 4 (left) to 12 (right) months of age. Activated microglia characterized by morphological changes (hypertrophy of cell body and shortened processes) selectively cluster around amyloid plaques at early ages. Increased amyloid load with age is associated with expansion of the microglial activation. The age-dependent accumulation of soluble Aβ oligomers induces the activation of the interplaque microglia in aged transgenic mice. (B) Illustrate the microglial response during the course of AD pathology in the hippocampus of human brains. Amyloid pathology is a late event in the hippocampus while tau pathology shows a very early onset. In Braak III–IV hippocampus, some amyloid plaques are present and they are surrounded by activated microglia, however in late stage AD (Braak V–VI) microglial-bare plaques are usually found. The high content of phospho-tau forms (intra- and/or extracellular) induces the degeneration of microglial cells in human Braak V–VI hippocampus.
Figure 2 Dissimilar progressions of hippocampal microglial response in APP/PS1 mice and human brains. (A) Illustrate the age-dependent microglial activation in the amyloidogenic model from 4 (left) to 12 (right) months of age. Activated microglia characterized by morphological changes (hypertrophy of cell body and shortened processes) selectively cluster around amyloid plaques at early ages. Increased amyloid load with age is associated with expansion of the microglial activation. The age-dependent accumulation of soluble Aβ oligomers induces the activation of the interplaque microglia in aged transgenic mice. (B) Illustrate the microglial response during the course of AD pathology in the hippocampus of human brains. Amyloid pathology is a late event in the hippocampus while tau pathology shows a very early onset. In Braak III–IV hippocampus, some amyloid plaques are present and they are surrounded by activated microglia, however in late stage AD (Braak V–VI) microglial-bare plaques are usually found. The high content of phospho-tau forms (intra- and/or extracellular) induces the degeneration of microglial cells in human Braak V–VI hippocampus.CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

Self-check

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

The self-check needs the paper’s full text.

Citations

Cites

Show all 53 references

Research works printed but not linked: 1

  1. Yeh, 2017, TREM2, microglia, and neurodegenerative diseases, Trends Mol. Med., 23, 512, 10.1016/j.molmed.2017.03.008 · DOI · Paper page

Cited by

Sorted by citations

See all 231

Related

Metadata

Authors
Navarro, V., Sanchez-Mejias, E., Jimenez, S., Muñoz-Castro, C., Sanchez-Varo, R., Davila, J. C., Vizuete, M., Gutierrez, A., & Vitorica, J.
Affiliations
Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
ORCID
Venue
Frontiers in Aging Neuroscience
Publisher
Frontiers Media SA
Published
2018-05-11
Volume
10
Pages
140-140
ISSN
1663-4365 (ISSN-L)
DOI
10.3389/fnagi.2018.00140
PMC
PMC5958192
OpenAlex
W2799331265
Cited by
229
References
53
Citations by year
2026: 11 · 2025: 13 · 2024: 33 · 2023: 35 · 2022: 32 · 2021: 31 · 2020: 43 · 2019: 27 · 2018: 3
FWCI
11.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Aging Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-nd)
  • RISalud Institutional Health Repository of Andalucía (submittedVersion, cc-by)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Deposito de Investigacion Universidad de Sevilla (University of Seville) (submittedVersion, cc-by-nc-nd)
  • Repositorio Institucional de la Universidad de Málaga (University of Málaga) (submittedVersion, cc-by)
Funders
  • Instituto de Salud Carlos III (PI15/00957 and PI15/00796)
  • Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía (CTS-2035)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
microglia, Alzheimer's disease, microglial activation, amyloid plaques, hippocampus, Braak stages, phosphorylated tau, dentate gyrus, neuroinflammation, regional heterogeneity

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.

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.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review