Astrocyte reactivity influences amyloid-β effects on tau pathology in preclinical Alzheimer’s disease
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Abstract
An unresolved question for the understanding of Alzheimer’s disease (AD) pathophysiology is why a significant percentage of amyloid-β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash Aβ effects in pathological tau phosphorylation. Here, in a biomarker study across three cohorts ( n = 1,016), we tested whether astrocyte reactivity modulates the association of Aβ with tau phosphorylation in CU individuals. We found that Aβ was associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity (Ast + ). Cross-sectional and longitudinal tau–positron emission tomography analyses revealed an AD-like pattern of tau tangle accumulation as a function of Aβ only in CU Ast + individuals. Our findings suggest astrocyte reactivity as an important upstream event linking Aβ with initial tau pathology, which may have implications for the biological definition of preclinical AD and for selecting CU individuals for clinical trials.
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Astrocyte activation leading to a chronic inflammatory response is considered to be one of the important pathological processes in AD.
“is considered to be one of the important pathological processes in AD”
From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [7]
The Main section describes astrocyte reactivity as one of the earliest abnormalities in AD, and the Discussion links it to early tau pathology in preclinical AD (page numbers unavailable). The paper does not establish that astrocyte activation leads to a chronic inflammatory response; searches for chronic inflammation and neuroinflammation did not find that link. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAstrocyte activation leading to a chronic inflammatory response has been proposed as a mechanism linking Aβ accumulation and tau pathology.
“Astrocyte activation leading to a chronic inflammatory response has been proposed as a mechanism linking Aβ accumulation and tau pathology (7)”
From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [7]
The Discussion reports that astrocyte reactivity plays a role in the association between Aβ and early tau phosphorylation in preclinical Alzheimer’s disease. It does not establish that astrocyte activation leads to a chronic inflammatory response or identify that response as the linking mechanism. (LLM, conf=0.86)
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“…mechanism underlying our findings that Aβ-mediated astrocyte signaling (for example, through cytokines, caspases and reactive oxygen species) induces tau pathology 3,13,29 , which is corroborated by studies showing that the suppression of this signaling is able to halt tau phosphorylation 17 .”
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- Authors
- Bellaver, B., Povala, G., Ferreira, P. C. L., Ferrari-Souza, J. P., Leffa, D. T., Lussier, F. Z., Benedet, A. L., Ashton, N. J., Triana-Baltzer, G., Kolb, H. C., Tissot, C., Therriault, J., Servaes, S., Stevenson, J., Rahmouni, N., Lopez, O. L., Tudorascu, D. L., Villemagne, V. L., Ikonomovic, M. D., Gauthier, S., Zimmer, E. R., Zetterberg, H., Blennow, K., Aizenstein, H. J., Klunk, W. E., Snitz, B. E., Maki, P., Thurston, R. C., Cohen, A. D., Ganguli, M., Karikari, T. K., Rosa-Neto, P., & Pascoal, T. A.
- Affiliations
- Universidade Federal do Rio Grande do Sul (BR)
- University of Pittsburgh (US)
- University of Gothenburg (SE)
- King's College London (GB)
- Centre intégré universitaire de santé et de services sociaux de l'Ouest-de-l’Île-de-Montréal (CA)
- University of Wisconsin–Madison (US)
- Sahlgrenska University Hospital (SE)
- University of Illinois Chicago (US)
- Corresponding author
- Pascoal, Tharick A.
- ORCID
- Bellaver, Bruna
- Povala, Guilherme
- Ferreira, Pamela C. L.
- Leffa, Douglas T.
- Lussier, Firoza Z.
- Benedet, Andréa L.
- Ashton, Nicholas J.
- Kolb, Hartmuth C.
- Tissot, Cécile
- Therriault, Joseph
- Servaes, Stijn
- Stevenson, Jenna
- Rahmouni, Nesrine
- Lopez, Oscar L.
- Tudorascu, Dana L.
- Villemagne, Victor L.
- Gauthier, Serge
- Zimmer, Eduardo R.
- Zetterberg, Henrik
- Blennow, Kaj
- Aizenstein, Howard J.
- Klunk, William E.
- Snitz, Beth E.
- Maki, Pauline
- Thurston, Rebecca C.
- Cohen, Ann D.
- Ganguli, Mary
- Karikari, Thomas K.
- Rosa-Neto, Pedro
- Pascoal, Tharick A.
- Venue
- Nature Medicine
- Published
- 2023-05-29
- Volume
- 29
- Issue
- 7
- Pages
- 1775-1781
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC10353939
- OpenAlex
- W4378713804
- Cited by
- 319
- References
- 10
- Citations by year
- 2026: 69 · 2025: 111 · 2024: 114 · 2023: 25
- FWCI
- 56.25
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Medicine (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion, cc-by)
- PubMed Central (submittedVersion, cc-by)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-sa)
- Funders
- Alzheimer's Association (ADSF-21-831377-C, ADSF‐21‐831376‐C, -21-850325, ADSF-21-831376-C, ADSF-21-831381-C and ADSF-21-831377-C, #ADSF-21-831381-C, AARGD-21-850670, AARFD-22-974627, 850325, AACSF-20-648075, -21- 831377-C, AARF-21-850325)
- Alzheimer's Drug Discovery Foundation (2016862, FO2017-0243, 201809, ADSF-21-831381-C, 2017-00915, UKDRI-1003, #ALFGBG-715986, ZEN-21-848495, 201809–2016862, ADSF-21-831377-C, 860197, JPND2019-466-236, JPND2021-00694, #ADSF-21-831376-C)
- BrightFocus Foundation (AF-930627, A2020812F)
- Familjen Erling-Perssons Stiftelse (860197)
- Gun och Bertil Stohnes Stiftelse
- Demensförbundet
- Stiftelsen för Gamla Tjänarinnor (FO2022‐0270, 860197)
- Weston Brain Institute
- EU Joint Programme – Neurodegenerative Disease Research (JPND 2021-00694, JPND2019-466-236)
- Consortium canadien en neurodégénérescence associée au vieillissement
- European Commission (101,053,962, JPND2021‐00694, HORIZON2020, ALFGBG-71320, JPND2019‐466‐236, 860197)
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (88887, 88887.336490/2019‐00)
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Hjärnfonden (#FO2022-0270, #FO2020-0240, JPND2019-466-236)
- Vetenskapsrådet (#101053962, 2021-03244, 2017-00915, 2022-01018, ALFGBG‐71320, 2022-00732, JPND2019-466-236)
- Alzheimerfonden (#AF-930627, #AF‐968270, AF-930351, AF‐939721)
- International Society for Neurochemistry
- Instituto Serrapilheira
- UK Dementia Research Institute (#2017-00915)
- Olav Thon Stiftelsen
- National Institutes of Health (1rf1ag052525-01a1)
- Parkinsonfonden
- HORIZON EUROPE Framework Programme (101053962, 860197)
- Canadian Institutes of Health Research (#MOP-11-51-31, 201809, 152985, 159815, RFN 152,985, 162303, MOP-11-51-31; RFN 152985)
- Fonds de Recherche du Québec - Santé (2020-VICO-279314)
- National Institute on Aging (R01AG052521, R01AG052446, P01AG025204, RF1AG025516, P01AG014449, RF1 AG052525, R01AG052528, RF1AG053504, R37AG023651, P30AG066468, R01AG073267, R01AG075336, R01AG053504)
- National Heart, Lung, and Blood Institute (R01HL105647, K24HL123565)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- astrocyte activation, amyloid-beta, tau phosphorylation, preclinical Alzheimer's disease, cognitively unimpaired individuals, tau tangles, plasma biomarkers, tau PET, astrocytes, clinical trial selection
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