Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies
Open accessPublished version of a preprint
Abstract
β-amyloid (Aβ) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer’s disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, Aβ-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z -score deviations for 246 brain regions were calculated and biomarker contributions of Aβ (A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional Aβ (AD: β T = 0.412 ± 0.196 vs. β A = 0.142 ± 0.123, p < 0.001; AD-CBS: β T = 0.385 ± 0.176 vs. β A = 0.131 ± 0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (β T = 0.418 ± 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and Aβ related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neurodegenerative diseases.
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Misfolded proteins and protein aggregates, including tau, Aβ, α-synuclein, mutant huntingtin, TDP-43, SOD1, and FUS induce microglial activation and neuroinflammation.
“Numerous studies have reported that misfolded proteins and protein aggregates, including tau,136–139 Aβ,138,140 α-synuclein,141–144 mutant huntingtin,145 TDP-43,132,146 superoxide dismutase 1 (SOD1),147–149 and fused in sarcoma (FUS)150 induce microglial activation and neuroinflammation.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [139]
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References 89 · Cited by 40
Research works printed but not linked: 4
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- Authors
- Finze, A., Biechele, G., Rauchmann, B.-S., Franzmeier, N., Palleis, C., Katzdobler, S., Weidinger, E., Guersel, S., Schuster, S., Harris, S., Schmitt, J., Beyer, L., Gnörich, J., Lindner, S., Albert, N. L., Wetzel, C. H., Rupprecht, R., Rominger, A., Danek, A., Burow, L., Kurz, C., Tato, M., Utecht, J., Papazov, B., Zaganjori, M., Trappmann, L.-K., Goldhardt, O., Grimmer, T., Haeckert, J., Janowitz, D., Buerger, K., Keeser, D., Stoecklein, S., Dietrich, O., Morenas-Rodriguez, E., Barthel, H., Sabri, O., Bartenstein, P., Simons, M., Haass, C., Höglinger, G. U., Levin, J., Perneczky, R., & Brendel, M.
- Affiliations
- LMU Klinikum (DE)
- Munich Cluster for Systems Neurology (DE)
- German Center for Neurodegenerative Diseases (DE)
- University of Regensburg (DE)
- University Hospital of Bern (CH)
- TUM Klinikum (DE)
- University of Augsburg (DE)
- Institut für Schlaganfall- und Demenzforschung (DE)
- Leipzig University (DE)
- Corresponding author
- Brendel, Matthias
- ORCID
- Finze, Anika
- Biechele, Gloria
- Rauchmann, Boris-Stephan
- Franzmeier, Nicolai
- Palleis, Carla
- Katzdobler, Sabrina
- Weidinger, Endy
- Guersel, Selim
- Schuster, Sebastian
- Harris, Stefanie
- Schmitt, Julia
- Beyer, Leonie
- Gnörich, Johannes
- Lindner, Simon
- Albert, Nathalie L.
- Wetzel, Christian H.
- Rupprecht, Rainer
- Rominger, Axel
- Danek, Adrian
- Kurz, Carolin
- Papazov, Boris
- Zaganjori, Mirlind
- Goldhardt, Oliver
- Grimmer, Timo
- Haeckert, Jan
- Janowitz, Daniel
- Keeser, Daniel
- Stoecklein, Sophia
- Dietrich, Olaf
- Barthel, Henryk
- Sabri, Osama
- Simons, Mikael
- Haass, Christian
- Höglinger, Günter U.
- Levin, Johannes
- Perneczky, Robert
- Brendel, Matthias
- Venue
- Molecular Psychiatry
- Published
- 2023-07-26
- Volume
- 28
- Issue
- 10
- Pages
- 4438-4450
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC10827660
- OpenAlex
- W4385274446
- Cited by
- 40
- References
- 89
- Citations by year
- 2026: 4 · 2025: 14 · 2024: 18 · 2023: 4
- FWCI
- 4.11
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Molecular Psychiatry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, other-oa)
- OPUS (Augsburg University) (submittedVersion, cc-by)
- mediaTUM (Technical University of Munich) (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion, other-oa)
- Funders
- Stiftung VERUM
- Alzheimer Forschung Initiative (19063p)
- Innovative Health Initiative
- National Institute for Health and Care Research (NIHR203321)
- University of Cambridge
- European Commission (101132356)
- Deutsche Forschungsgemeinschaft (HO2402/18-1, 422182557, EXC 2145, FOR-2858, EXC 2145SyNergy, HO2402/18-1MSAomics, 403161218, 390857198, 421887978, 422179811, EXC2155, 39087428, 422188432)
- Bundesministerium für Bildung und Forschung (01KU1403A EpiPD; 01EK1605A HitTau, 01EK1605A, 01KU1403A EpiPD, 01EK1605A HitTau, 01DH18025, 01KU1403A)
- Friedrich-Baur-Stiftung
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- microglial activation, tau pathology, amyloid-beta, neuroinflammation, primary tauopathies, Alzheimer's disease, TSPO PET, gray matter atrophy, soluble TREM2, clinical performance
- MeSH terms
- Neuroinflammatory Diseases, Alzheimer Disease, Atrophy, Humans, Biomarkers, Amyloid beta-Peptides, tau Proteins, Microglia, Receptors, GABA, Tauopathies
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