Microglial activation and tau propagate jointly across Braak stages.

TitleMicroglial activation and tau propagate jointly across Braak stages.
Publication TypeJournal Article
Year of Publication2021
AuthorsPascoal TA, Benedet AL, Ashton NJ, Kang MSu, Therriault J, Chamoun M, Savard M, Lussier FZ, Tissot C, Karikari TK, Ottoy J, Mathotaarachchi S, Stevenson J, Massarweh G, Schöll M, de Leon MJ, Soucy J-P, Edison P, Blennow K, Zetterberg H, Gauthier S, Rosa-Neto P
JournalNat Med
Date Published2021 09
KeywordsAdult, Aged, Aging, Alzheimer Disease, Amyloid beta-Peptides, Brain, Cognitive Dysfunction, Female, Gene Expression Regulation, Humans, Male, Membrane Glycoproteins, Microglia, Neurofibrillary Tangles, Positron-Emission Tomography, Receptors, Immunologic, tau Proteins

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 ([C]PBR28), amyloid-β (Aβ) ([F]AZD4694) and tau ([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 [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.

Alternate JournalNat Med
PubMed ID34446931
Grant ListMOP-11-51-31 / / CIHR / Canada
FRN 152985 / / CIHR / Canada