Esti Yager–Lotem, Israel
Ben-Gurion University of the Negev Clinical Biochemistry and PharmacologyAuthor Of 1 Presentation
DISSECTING THE COMPLEXITY OF ASTROCYTE HETEROGENEITY IN THE AGED HUMAN BRAIN
Abstract
Aims
Neuroinflammation plays a critical role in the pathophysiology of neurodegenerative disorders, and astrocyte activity impairment has been implicated in the initiation and progression of Alzheimer’s Disease (AD). However, understanding the astrocyte heterogeneity in the aged human brain and identifying the subtypes relevant to AD remain challenging due inter-individual variability. This study aims to characterize astrocyte heterogeneity among aged individuals with or without AD and investigate the association of astrocyte subtypes with AD traits at RNA and protein levels.
Methods
We used single nucleus RNASeq (snRNAseq) to characterize subtypes of astrocytes in the dorsolateral prefrontal cortex of 24 aged individuals with or without AD from the Religious Orders Study and the Rush Memory and Aging Project cohorts. Then, a marker for each cluster was selected and stained by immunohistochemistry on post-mortem brain tissue from the same 24 individuals.
Results
We identified five different astrocyte subtypes that we classified in four categories: homeostatic, reactive, fibrous-like and inflammatory. The snRNAseq data revealed an association between increased fibrous-like astrocytes and cognitive decline, especially in individuals with AD pathology. No significant association was detected between AD traits and other astrocytes subtypes. Both snRNAseq and immunohistochemistry demonstrated that not all astrocyte subtypes were detected in all 24 individuals. SOCS3, a marker for reactive-like astrocyte was only detected in few individuals at RNA and protein levels.
Conclusions
Fibrous-like astrocyte subtype was associated with cognitive decline in AD. Further, combined snRNAseq and immunohistochemistry demonstrated the complexity of astrocyte heterogeneity, that is driven by high inter-individual variability.