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Cited by 119Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

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Ultrastructural evidence of microglial heterogeneity in Alzheimer’s disease amyloid pathology

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El Hajj, Hassan, Savage, Julie C., Bisht, Kanchan, Parent, Martin, Vallières, Luc, Rivest, Serge, Tremblay, Marie-Ève·2019·Journal of Neuroinflammation
DOI 10.1186/s12974-019-1473-9PMC PMC6469225
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Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease, characterized by the deposition of extracellular fibrillar amyloid β (fΑβ) and the intracellular accumulation of neurofibrillary tangles. As AD progresses, Aβ drives a robust and prolonged inflammatory response via its recognition by microglia, the brain’s immune cells. Microglial reactivity to fAβ plaques may impair their normal surveillance duties, facilitating synaptic loss and neuronal death, as well as cognitive decline in AD. In the current study, we performed correlative light, transmission, and scanning electron microscopy to provide insights into microglial structural and functional heterogeneity. We analyzed microglial cell bodies and processes in areas containing fAβ plaques and neuronal dystrophy, dystrophy only, or appearing healthy, among the hippocampus CA1 of 14-month-old APPSwe-PS1Δe9 mice versus wild-type littermates. Our quantitative analysis revealed that microglial cell bodies in the AD model mice were larger and displayed ultrastructural signs of cellular stress, especially nearby plaques. Microglial cell bodies and processes were overall less phagocytic in AD model mice. However, they contained increased fibrillar materials and non-empty inclusions proximal to plaques. Microglial cell bodies and processes in AD model mice also displayed reduced association with extracellular space pockets that contained debris. In addition, microglial processes in healthy subregions of AD model mice encircled synaptic elements more often compared with plaque-associated processes. These observations in mice were qualitatively replicated in post-mortem hippocampal samples from two patients with AD (Braak stage 5). Together, our findings identify at the ultrastructural level distinct microglial transformations common to mouse and human in association with amyloid pathology.

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Figures

Fig. 1 Defining dystrophic and plaque-associated neuropil areas. a An example EM image displaying a microglial cell body in plaque- and dystrophic-associated region of the ventral hippocampus CA1 in APPSwe-PS1Δe9 model mice. b Two microglial cell bodies and a microglial process showing IBA1 immunoreactivity surround a fAβ plaque and associated dystrophy. c A microglial cell body contacts both a dystrophic neurite and a fAβ plaque while a second microglial cell contacts a blood vessel. d A microglial cell body and its proximal process displaying IBA1 immunoreactivity encircle a fAβ plaque. Other microglial processes, discontinuous to the cell body in ultrathin section, can also be seen. bv blood vessel, m microglia. Dystrophy and fAβ plaques are labeled throughout the figure
Fig. 1 Defining dystrophic and plaque-associated neuropil areas. a An example EM image displaying a microglial cell body in plaque- and dystrophic-associated region of the ventral hippocampus CA1 in APPSwe-PS1Δe9 model mice. b Two microglial cell bodies and a microglial process showing IBA1 immunoreactivity surround a fAβ plaque and associated dystrophy. c A microglial cell body contacts both a dystrophic neurite and a fAβ plaque while a second microglial cell contacts a blood vessel. d A microglial cell body and its proximal process displaying IBA1 immunoreactivity encircle a fAβ plaque. Other microglial processes, discontinuous to the cell body in ultrathin section, can also be seen. bv blood vessel, m microglia. Dystrophy and fAβ plaques are labeled throughout the figureCC BY · PubMed Central
Fig. 2 Microglial ultrastructure is changed by proximity to fAβ plaques. a EM image from a WT control animal showing oval shaped IBA1-positive microglial cell body contacting extracellular space pocket and axon terminal in the ventral hippocampus CA1. b EM image of a plaque-associated microglial cell body that contains lipidic inclusions, lipofuscin granule, and lysosome, as well as contacting extracellular space pocket. c Microglial processes in an ultrastructurally healthy subregion of APPSwe-PS1Δe9 mouse model, touching or encircling various types of synaptic elements. d dendrite, Ex extracellular space pocket containing debris, Lg lipofuscin granule, Lip lipidic inclusion, Ly lysosome, m microglia, mt mitochondrion, s dendritic spine, t axon terminal. d Change in microglial cell body area of WT controls compared to APPSwe-PS1Δe9 animals. e Change in microglial cell body area in APP-H, APP-D, and APP-P subregions. f Change in the microglial process circularity in WT and APPSwe-PS1Δe9 animals. g Change in the microglial process solidity in WT and APPSwe-PS1Δe9 animals. n = 50 processes per condition for APP-H, APP-D, and APP-P and 70 processes per animal for WT animals, n = 7–15 cells per condition for all conditions, and data was collected from N = 3–4 animals per condition. All error bars are mean ± SEM. WT levels are shown on the subregion graphs by a gray horizontal line. *p < 0.05 difference from WT, ~p < 0.05 difference from APP-H
Fig. 2 Microglial ultrastructure is changed by proximity to fAβ plaques. a EM image from a WT control animal showing oval shaped IBA1-positive microglial cell body contacting extracellular space pocket and axon terminal in the ventral hippocampus CA1. b EM image of a plaque-associated microglial cell body that contains lipidic inclusions, lipofuscin granule, and lysosome, as well as contacting extracellular space pocket. c Microglial processes in an ultrastructurally healthy subregion of APPSwe-PS1Δe9 mouse model, touching or encircling various types of synaptic elements. d dendrite, Ex extracellular space pocket containing debris, Lg lipofuscin granule, Lip lipidic inclusion, Ly lysosome, m microglia, mt mitochondrion, s dendritic spine, t axon terminal. d Change in microglial cell body area of WT controls compared to APPSwe-PS1Δe9 animals. e Change in microglial cell body area in APP-H, APP-D, and APP-P subregions. f Change in the microglial process circularity in WT and APPSwe-PS1Δe9 animals. g Change in the microglial process solidity in WT and APPSwe-PS1Δe9 animals. n = 50 processes per condition for APP-H, APP-D, and APP-P and 70 processes per animal for WT animals, n = 7–15 cells per condition for all conditions, and data was collected from N = 3–4 animals per condition. All error bars are mean ± SEM. WT levels are shown on the subregion graphs by a gray horizontal line. *p < 0.05 difference from WT, ~p < 0.05 difference from APP-HCC BY · PubMed Central
Fig. 3 Distinct alterations in microglial interaction with the neuropil, including synaptic structures, in APPSwe-PS1Δe9 animals. a EM image of an IBA1-positive microglial cell body in the ventral hippocampus CA1 of a WT control making numerous contacts with extracellular space pockets containing debris. b EM image of an IBA1-positive microglial cell body in a section containing dystrophy, making contact with extracellular space pockets and an axon terminal. A non-empty phagocytic inclusion is pseudocolored in green. c An IBA1-positive microglial process makes contacts with extracellular space pockets containing debris, as well as various dendrites and axon terminals. d IBA1-positive microglial process encircling degraded elements in the APP-H subregion. e, f IBA1-positive microglial processes encircling synapses between axon terminals and dendritic spines in APP-H and APP-D subregions. d dendrite, De degraded element, Ex extracellular space pocket containing debris, m microglia, s dendritic spine, t axon terminal. g Microglial cell bodies interact less with extracellular debris in APPSwe-PS1Δe9 mice. h Microglial cell bodies in APP-H regions interact less with extracellular debris than those in APP-D regions in APPSwe-PS1Δe9 mice. i Microglial processes in APPSwe-PS1Δe9 mice interact less with extracellular debris than WT processes. j–l Processes in APPSwe-PS1Δe9 mice encircle more synaptic elements (j) including (k) axon terminals, and (l) dendritic spines. m Processes in APP-P associated regions encircle fewer synaptic elements than processes in APP-H subregion. n Only microglial processes in APP-P subregion encircle Aβ (mean ± SEM). WT levels are shown on the subregion graphs by a gray horizontal line. n = 50 processes per condition for APP-H, APP-D, and APP-P and 70 processes per animal for WT animals, n = 7–15 cells per condition for all conditions, and data was collected from N = 3–4 animals per condition. * denotes difference from WT, ~ denotes difference from APP-H, # denotes difference from APP-P *,~,#p < 0.05; **p < 0.01; ***p < 0.001
Fig. 3 Distinct alterations in microglial interaction with the neuropil, including synaptic structures, in APPSwe-PS1Δe9 animals. a EM image of an IBA1-positive microglial cell body in the ventral hippocampus CA1 of a WT control making numerous contacts with extracellular space pockets containing debris. b EM image of an IBA1-positive microglial cell body in a section containing dystrophy, making contact with extracellular space pockets and an axon terminal. A non-empty phagocytic inclusion is pseudocolored in green. c An IBA1-positive microglial process makes contacts with extracellular space pockets containing debris, as well as various dendrites and axon terminals. d IBA1-positive microglial process encircling degraded elements in the APP-H subregion. e, f IBA1-positive microglial processes encircling synapses between axon terminals and dendritic spines in APP-H and APP-D subregions. d dendrite, De degraded element, Ex extracellular space pocket containing debris, m microglia, s dendritic spine, t axon terminal. g Microglial cell bodies interact less with extracellular debris in APPSwe-PS1Δe9 mice. h Microglial cell bodies in APP-H regions interact less with extracellular debris than those in APP-D regions in APPSwe-PS1Δe9 mice. i Microglial processes in APPSwe-PS1Δe9 mice interact less with extracellular debris than WT processes. j–l Processes in APPSwe-PS1Δe9 mice encircle more synaptic elements (j) including (k) axon terminals, and (l) dendritic spines. m Processes in APP-P associated regions encircle fewer synaptic elements than processes in APP-H subregion. n Only microglial processes in APP-P subregion encircle Aβ (mean ± SEM). WT levels are shown on the subregion graphs by a gray horizontal line. n = 50 processes per condition for APP-H, APP-D, and APP-P and 70 processes per animal for WT animals, n = 7–15 cells per condition for all conditions, and data was collected from N = 3–4 animals per condition. * denotes difference from WT, ~ denotes difference from APP-H, # denotes difference from APP-P *,~,#p < 0.05; **p < 0.01; ***p < 0.001CC BY · PubMed Central
Fig. 4 Distinct changes in microglial phagolysosomal system of APPSwe-PS1Δe9 animals. a–c Example of IBA1-positive microglial cell bodies containing empty inclusions, non-empty inclusions (pseudocolored in green), or fibrillar materials in wild-type (WT; a), APP-D (b), or APP-P (c) subregions of ventral hippocampus CA1. d Quantification of fibrillar materials phagocytosis by microglial cell bodies in APPSwe-PS1Δe9 mice. e Quantification of cell bodies containing empty phagocytic inclusions in APPSwe-PS1Δe9 mice. f Only microglial cell bodies in APP-P regions contained fibrillar materials. g Cell bodies in APP-P regions contained increased numbers of non-empty phagocytic inclusions. h–j IBA1-positive microglial processes containing various phagocytic inclusions in APP-P and APP-D subregions. k Quantification of microglial process inclusions in WT and APPSwe-PS1Δe9 mice. l Quantification of microglial processes containing empty inclusions in APPSwe-PS1Δe9 mice. m Only microglial processes in APP-P regions contained fibrillar materials. n Quantification of lysosome numbers in APP-H, APP-D, and APP-P subregions associated microglial processes. d dendrite, Ep empty phagocytic inclusion, dn dystrophic neurite, fm fibrillar material, Ex extracellular space pocket containing debris, m microglia, mt mitochondrion, s dendritic spine, t axon terminal. Error bars represent mean ± SEM. WT levels are shown on the subregion graphs by a gray horizontal line. n = 50 processes per condition for APP-H, APP-D, and APP-P and 70 processes per animal for WT animals, n = 7–15 cells per condition for all conditions, and data was collected from N = 3–4 animals per condition. * denotes difference from WT, ~ denotes difference from APP-H, # denotes difference from APP-P *,~p < 0.05; **,~~p < 0.01; ***,~~~,###p < 0.001
Fig. 4 Distinct changes in microglial phagolysosomal system of APPSwe-PS1Δe9 animals. a–c Example of IBA1-positive microglial cell bodies containing empty inclusions, non-empty inclusions (pseudocolored in green), or fibrillar materials in wild-type (WT; a), APP-D (b), or APP-P (c) subregions of ventral hippocampus CA1. d Quantification of fibrillar materials phagocytosis by microglial cell bodies in APPSwe-PS1Δe9 mice. e Quantification of cell bodies containing empty phagocytic inclusions in APPSwe-PS1Δe9 mice. f Only microglial cell bodies in APP-P regions contained fibrillar materials. g Cell bodies in APP-P regions contained increased numbers of non-empty phagocytic inclusions. h–j IBA1-positive microglial processes containing various phagocytic inclusions in APP-P and APP-D subregions. k Quantification of microglial process inclusions in WT and APPSwe-PS1Δe9 mice. l Quantification of microglial processes containing empty inclusions in APPSwe-PS1Δe9 mice. m Only microglial processes in APP-P regions contained fibrillar materials. n Quantification of lysosome numbers in APP-H, APP-D, and APP-P subregions associated microglial processes. d dendrite, Ep empty phagocytic inclusion, dn dystrophic neurite, fm fibrillar material, Ex extracellular space pocket containing debris, m microglia, mt mitochondrion, s dendritic spine, t axon terminal. Error bars represent mean ± SEM. WT levels are shown on the subregion graphs by a gray horizontal line. n = 50 processes per condition for APP-H, APP-D, and APP-P and 70 processes per animal for WT animals, n = 7–15 cells per condition for all conditions, and data was collected from N = 3–4 animals per condition. * denotes difference from WT, ~ denotes difference from APP-H, # denotes difference from APP-P *,~p < 0.05; **,~~p < 0.01; ***,~~~,###p < 0.001CC BY · PubMed Central
Fig. 5 Microglia in APPSwe-PS1Δe9 animals display increased signs of cellular stress. a Example of IBA1-positive cell body imaged in the ventral hippocampus CA1 of the APP-P subregion that displays ER dilation, a lipidic inclusion and lipofuscin granules. b Example of microglial process in the APP-P subregion showing ER dilation. c IBA1-positive microglial cell body contacting extracellular space pockets with debris and containing lipidic inclusions and lipofuscin granules. d Microglial cell process containing a lysosome and a lipidic inclusion. d dendrite, er endoplasmic reticulum, Ex extracellular space pocket containing debris, Lg lipofuscin granule, Lip lipidic inclusion, Lys lysosome, m microglia, ma myelinated axon, mt mitochondrion, s dendritic spine, t axon terminal. e Quantification of dilated ER in microglial cell bodies from APP-H, APP-D, and APP-P subregions of APPSwe-PS1Δe9 mice. f Microglial processes in APPSwe-PS1Δe9 animals are more likely to contain lipidic inclusions than those in WT animals. g Quantification of lipid body inclusions in microglial processes from APP-H, APP-D, and APP-P subregions. n = 50 processes per condition for APP-H, APP-D, and APP-P and 70 processes per animal for WT animals, n = 7–15 cells per condition for all conditions, and data was collected from N = 3–4 animals per condition. Error bars represent mean ± SEM. WT levels are shown on the subregion graphs by a gray horizontal line. #p < 0.05; ***,###p < 0.001. * denotes difference from WT animal, # denotes difference from APP-P region
Fig. 5 Microglia in APPSwe-PS1Δe9 animals display increased signs of cellular stress. a Example of IBA1-positive cell body imaged in the ventral hippocampus CA1 of the APP-P subregion that displays ER dilation, a lipidic inclusion and lipofuscin granules. b Example of microglial process in the APP-P subregion showing ER dilation. c IBA1-positive microglial cell body contacting extracellular space pockets with debris and containing lipidic inclusions and lipofuscin granules. d Microglial cell process containing a lysosome and a lipidic inclusion. d dendrite, er endoplasmic reticulum, Ex extracellular space pocket containing debris, Lg lipofuscin granule, Lip lipidic inclusion, Lys lysosome, m microglia, ma myelinated axon, mt mitochondrion, s dendritic spine, t axon terminal. e Quantification of dilated ER in microglial cell bodies from APP-H, APP-D, and APP-P subregions of APPSwe-PS1Δe9 mice. f Microglial processes in APPSwe-PS1Δe9 animals are more likely to contain lipidic inclusions than those in WT animals. g Quantification of lipid body inclusions in microglial processes from APP-H, APP-D, and APP-P subregions. n = 50 processes per condition for APP-H, APP-D, and APP-P and 70 processes per animal for WT animals, n = 7–15 cells per condition for all conditions, and data was collected from N = 3–4 animals per condition. Error bars represent mean ± SEM. WT levels are shown on the subregion graphs by a gray horizontal line. #p < 0.05; ***,###p < 0.001. * denotes difference from WT animal, # denotes difference from APP-P regionCC BY · PubMed Central
Fig. 6 Microglial ultrastructure in post-mortem hippocampal samples from two human AD patients. a, b Examples of IBA1-immunopositive microglial cell bodies and processes surrounding fAβ plaques in the post-mortem hippocampus from an individual diagnosed with AD (Braak stage 5). c–e Insets from A and B, showing: c a microglial cell body contacting a dystrophic neurite, d a microglial process encircling two dystrophic neurites, and e another microglial process wrapping around other neuropil elements. f–j IBA1-immunopositive microglial cell body and processes from post-mortem hippocampal tissue from a second individual diagnosed with AD (also Braak stage 5). g–j Microglial processes seen making contacts with dystrophic neurites and dendritic spines, some of them receiving synapses from axon terminals, as well as containing phagocytic inclusions and lysosomes. dn dystrophic neurite, Ly lysosome, m microglia, mt mitochondrion, s dendritic spine, t axon terminal. Non-empty phagocytic inclusions are pseudocolored in green
Fig. 6 Microglial ultrastructure in post-mortem hippocampal samples from two human AD patients. a, b Examples of IBA1-immunopositive microglial cell bodies and processes surrounding fAβ plaques in the post-mortem hippocampus from an individual diagnosed with AD (Braak stage 5). c–e Insets from A and B, showing: c a microglial cell body contacting a dystrophic neurite, d a microglial process encircling two dystrophic neurites, and e another microglial process wrapping around other neuropil elements. f–j IBA1-immunopositive microglial cell body and processes from post-mortem hippocampal tissue from a second individual diagnosed with AD (also Braak stage 5). g–j Microglial processes seen making contacts with dystrophic neurites and dendritic spines, some of them receiving synapses from axon terminals, as well as containing phagocytic inclusions and lysosomes. dn dystrophic neurite, Ly lysosome, m microglia, mt mitochondrion, s dendritic spine, t axon terminal. Non-empty phagocytic inclusions are pseudocolored in greenCC BY · PubMed Central

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  1. International AD. World Alzheimer Report 2016; 2016. p. 1–140.
  2. Alzheimer Association. 2018 Alzheimer’s disease facts and figures. Alzheimer’s Dement. 2018;2018:1–88.
  3. Ferreira ST, Lourenco MV, Oliveira MM, De Felice FG. Soluble amyloid-beta oligomers as synaptotoxins leading to cognitive impairment in Alzheimer’s disease. Front Cell Neurosci. 2015;9:9498.
  4. Solé-Domènech S, Cruz DL, Capetillo-Zarate E, Maxfield FR. Ageing research reviews Ageing Research Reviews. Elsevier B.V; 2016;32:89–103.

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Metadata

Authors
El Hajj, H., Savage, J. C., Bisht, K., Parent, M., Vallières, L., Rivest, S., & Tremblay, M.-È.
Affiliations
  • Centre de recherche du CHU de Québec-Université Laval (CA)
  • Université Laval (CA)
Corresponding author
Tremblay, Marie-Ève
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2019-04-16
Volume
16
Issue
1
Pages
87-87
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/s12974-019-1473-9
PMC
PMC6469225
OpenAlex
W2946033659
Cited by
119
References
95
Citations by year
2026: 7 · 2025: 11 · 2024: 23 · 2023: 16 · 2022: 22 · 2021: 18 · 2020: 18 · 2019: 4
FWCI
6.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Fonds de recherche en santé du Québec
  • Lebanese Ministry of Education and Higher Education
  • Fondation du CHU de Québec
  • The Banting Research Foundation
  • The Scottish Rite Charitable Foundation of Canada
  • NEURON-ERANET
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
Alzheimer's disease, microglial heterogeneity, amyloid plaques, amyloid fibrils, APPswe/PS1ΔE9 mice, hippocampal CA1, microglial phagocytosis, neuronal dystrophy, Braak stages, neuroinflammation
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Animals, Hippocampus, Humans, Amyloid beta-Peptides, Microglia, Mice

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