Association of reactive astrogliosis and microglial activation with tau pathology in Alzheimer’s disease
João Pedro Ferrari‐Souza, Bruna Bellaver, Pamela C.L. Ferreira, Guilherme Povala, Firoza Z Lussier, Douglas Teixeira Leffa, Joseph Therriault, Cécile Tissot, Andrea Lessa Benedet, Carolina Soares, Cristiano Schaffer Aguzzoli, Hussein Zalzale, Francieli Rohden, Yi‐Ting Wang, Mira Chamoun, Stijn Servaes, Arthur C. Macedo, Marie Vermeiren, Gleb Bezgin, Min Su Kang, Jenna Stevenson, Nesrine Rahmouni, Vanessa Pallen, Nina Margherita Poltronetti, Diogo O. Souza, Jean‐Paul Soucy, Serge Gauthier, Gallen Triana‐Baltzer, Ziad S. Saad, Hartmuth C. Kolb, Lucas Porcello Schilling, Thomas K Karikari, Nicholas J. Ashton, Henrik Zetterberg, Kaj Blennow, Pedro Rosa‐Neto, Tharick A. Pascoal, Eduardo R Zimmer- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Glial contributions to Alzheimer’s disease (AD) etiology and progression have been increasingly recognized. Experimental and clinical evidence suggests that both microglial activation and astrocyte reactivity have pivotal roles in the progression of tau pathology. However, it remains to be elucidated how microglia and astrocytes complement each other in AD pathogenesis. Here, we tested the associations between reactive astrogliosis and microglial activation with tau phosphorylation and aggregation in individuals across the aging and AD spectrum.
Method
We studied 95 participants (14 cognitively unimpaired [CU] young, 46 CU elderly, and 35 cognitively impaired [CI]) from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. Individuals had available positron emission tomography (PET) for Aß ([18F]AZD4694), tau tangles ([18F]MK6240), and microglial activation ([11C]PBR28). We further assessed reactive astrogliosis (plasma glial fibrillary acidic protein [GFAP]) and pathological tau phosphorylation (plasma phosphorylated tau [p‐tau] at threonine 231, 181, and 217).
Result
Demographic characteristics of the study population are reported in Table 1. Regression analyses revealed that reactive astrogliosis and microglial activation were synergistically associated with higher plasma phosphorylated tau levels independently of Aß pathology in CU but not CI individuals (Figure 1A). On the other hand, no interactive effects of reactive astrogliosis and microglial activation on tau‐PET burden were observed in either CU or CI individuals (Figure 1B). Similar findings were observed in sensitivity analyses excluding CU young participants.
Conclusion
Our results suggest that reactive astrocytes and activated microglia have Aß‐independent synergistic effects on the early progression of AD pathophysiology by contributing to tau phosphorylation but not tau aggregation. These findings can help to better understand the complementary roles of glial cells in neurodegenerative diseases, as well as provide insights for the development novel therapeutic strategies for AD targeting the interplay between astrocyte and microglial reactivity.