Microglial activation and tau propagate jointly across Braak stages
Open accessAbstract
Compelling experimental evidence suggests that microglial activation is involved in the spread of tau tangles over the neocortex in Alzheimer's disease (AD). We tested the hypothesis that the spatial propagation of microglial activation and tau accumulation colocalize in a Braak-like pattern in the living human brain. We studied 130 individuals across the aging and AD clinical spectrum with positron emission tomography brain imaging for microglial activation ([11 C]PBR28), amyloid-β (Aβ) ([18 F]AZD4694) and tau ([18 F]MK-6240) pathologies. We further assessed microglial triggering receptor expressed on myeloid cells 2 (TREM2) cerebrospinal fluid (CSF) concentrations and brain gene expression patterns. We found that [11 C]PBR28 correlated with CSF soluble TREM2 and showed regional distribution resembling TREM2 gene expression. Network analysis revealed that microglial activation and tau correlated hierarchically with each other following Braak-like stages. Regression analysis revealed that the longitudinal tau propagation pathways depended on the baseline microglia network rather than the tau network circuits. The co-occurrence of Aβ, tau and microglia abnormalities was the strongest predictor of cognitive impairment in our study population. Our findings support a model where an interaction between Aβ and activated microglia sets the pace for tau spread across Braak stages.
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The activation of microglia by protein aggregates creates a feed-forward vicious cycle that aggravates neurodegeneration as activated microglia contribute to the propagation of tau, Aβ, α-synuclein, and TDP-43 into unaffected brain regions.
“Ultimately, the activation of microglia by these protein aggregates creates a feed-forward vicious cycle that aggravates neurodegeneration as activated microglia contribute to the propagation of tau, Aβ, α-synuclein, and TDP-43 into unaffected brain regions.159–164”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [162]
In AD and frontotemporal dementia, neuroinflammation and microglia activation potentiate the spreading of pathological tau neurofibrillary tangles.
“For example, in AD and frontotemporal dementia, neuroinflammation and microglia activation potentiate the spreading of pathological tau neurofibrillary tangles (83, 175).”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [175]
Microglial activation and tau accumulation propagate spatially in parallel, following brain circuits and staging of tau pathology in the brain of AD patients.
“In the brain of AD patients, microglial activation and tau accumulation propagate spatially in parallel, following brain circuits and staging of tau pathology [187].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [187]
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Activation of innate immune cGAS-STING pathway contributes to Alzheimer’s pathogenesis in 5×FAD mice
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TREM2 dependent and independent functions of microglia in Alzheimer’s disease
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White matter hyperintensities in Alzheimer's disease: Beyond vascular contribution
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“Abnormal microglia activation is one of the typical pathological features in AD patients [11,34].”
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Self-citationMicroglia: Friend and foe in tauopathy
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2021 marks a new era for Alzheimer's therapeutics
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- Authors
- Pascoal, T. A., Benedet, A. L., Ashton, N. J., Kang, M. S., Therriault, J., Chamoun, M., Savard, M., Lussier, F. Z., Tissot, C., Karikari, T. K., Ottoy, J., Mathotaarachchi, S., Stevenson, J., Massarweh, G., Schöll, M., de Leon, M. J., Soucy, J.-P., Edison, P., Blennow, K., Zetterberg, H., Gauthier, S., & Rosa-Neto, P.
- Affiliations
- University of Pittsburgh (US)
- King's College London (GB)
- Montreal Neurological Institute and Hospital (CA)
- Centre intégré universitaire de santé et de services sociaux de l'Ouest-de-l’Île-de-Montréal (CA)
- University of Gothenburg (SE)
- University of Antwerp (BE)
- UCL Queen Square Institute of Neurology (GB)
- Hammersmith Hospital (GB)
- Sahlgrenska University Hospital (SE)
- Corresponding author
- Pascoal, Tharick A.
- ORCID
- Pascoal, Tharick A.
- Benedet, Andrea L.
- Ashton, Nicholas J.
- Kang, Min Su
- Therriault, Joseph
- Chamoun, Mira
- Lussier, Firoza Z.
- Tissot, Cécile
- Karikari, Thomas K.
- Ottoy, Julie
- Mathotaarachchi, Sulantha
- Stevenson, Jenna
- Massarweh, Gassan
- Schöll, Michael
- Soucy, Jean-Paul
- Edison, Paul
- Blennow, Kaj
- Zetterberg, Henrik
- Gauthier, Serge
- Rosa-Neto, Pedro
- Venue
- Nature Medicine
- Published
- 2021-08-26
- Volume
- 27
- Issue
- 9
- Pages
- 1592-1599
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W3194048913
- Cited by
- 490
- References
- 91
- Citations by year
- 2026: 52 · 2025: 95 · 2024: 119 · 2023: 104 · 2022: 106 · 2021: 13
- FWCI
- 53.80
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-10-15)
- Open access
- green
- discovery.ucl.ac.uk
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Alzheimer’s Association (AACSF-20-648075)
- Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre (MOP-11-51-31, PR-N)
- Alzheimer’s Drug Discovery Foundation (RDAPB-201809-2016615)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- microglial activation, tau propagation, Braak stages, Alzheimer's disease, TREM2, amyloid-beta, [11C]PBR28, [18F]MK-6240, cognitive impairment, disease progression
- MeSH terms
- Adult, Aged, Aging, Alzheimer Disease, Brain, Female, Gene Expression Regulation, Humans, Male, Membrane Glycoproteins, Receptors, Immunologic, Amyloid beta-Peptides, Neurofibrillary Tangles, tau Proteins, Microglia, Positron-Emission Tomography, Cognitive Dysfunction
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