Determinants of astrocytic pathology in stem cell models of primary tauopathies

Acta Neuropathologica Communications

Research

Jordan N. Hook¹  Kimberly L. Fiock²  Marco M. Hefti³ 

[1] Department of Pathology, University of Iowa, 25 S Grand Ave MRC-108-A, 52240, Iowa City, IA, USA;Carver College of Medicine, University of Iowa, Iowa City, IA, USA;Department of Pathology, University of Iowa, 25 S Grand Ave MRC-108-A, 52240, Iowa City, IA, USA;Experimental Pathology Graduate Program, University of Iowa, Iowa City, IA, USA;Carver College of Medicine, University of Iowa, Iowa City, IA, USA;Department of Pathology, University of Iowa, 25 S Grand Ave MRC-108-A, 52240, Iowa City, IA, USA;Experimental Pathology Graduate Program, University of Iowa, Iowa City, IA, USA;Carver College of Medicine, University of Iowa, Iowa City, IA, USA;Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA;

关键词: Astrocytes;    Stem cells;    Tauopathy;    Tau;    Progressive supranuclear palsy;    Corticobasal degeneration;   

DOI  :  10.1186/s40478-023-01655-1

 received in 2023-08-07, accepted in 2023-09-24,  发布年份 2023

来源: Springer

【 摘 要 】

Astrocytic tau aggregates are seen in several primary and secondary tauopathies, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and chronic traumatic encephalopathy (CTE). In all of these diseases, astrocytic tau consists mostly of the longer (4R) tau isoform, even when adjacent neuronal aggregates consist of a mixture of 3- and 4R tau, as in CTE. Even the rare astrocytic tau aggregates seen in Pick’s disease appear to contain both 3R and 4R tau. The reasons for this, and the mechanisms by which astrocytic tau aggregates form, remain unclear. We used a combination of RNA in situ hybridization and immunofluorescence in post-mortem human brain tissue, as well as tau uptake studies in human stem cell-derived astrocytes, to determine the origins of astrocytic tau in 4R tauopathies. We found no differences in tau mRNA expression between diseases or between tau positive and negative astrocytes within PSP. We then found that stem cell-derived astrocytes preferentially take up long isoform (4R) recombinant tau and that this uptake is impaired by induction of reactivity with inflammatory stimuli or nutritional stress. Astrocytes exposed to either 3R or 4R tau also showed downregulation of genes related to astrocyte differentiation. Our findings suggest that astrocytes preferentially take up neuronal 4R tau from the extracellular space, potentially explaining why 4R tau is the predominant isoform in astrocytic tau aggregates.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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