Spatial and single-cell transcriptomics reveal the reorganization of cerebellar microglia with aging.

Andy P Tsai, Douglas E Henze, Eduardo Ramirez Lopez, James Haberberger, Chuanpeng Dong, Nannan Lu, Micaiah Atkins, Emma K Costa, Amelia Farinas, Hamilton Se-Hwee Oh, Patricia Moran-Losada, Yann Le Guen, Alina Isakova, Stephen R Quake, Tony Wyss-Coray

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. · pubmed

Paper

Abstract

The cerebellum, essential for motor coordination and increasingly recognized for its role in cognition, is typically considered more resilient to aging and largely spared from hallmark Alzheimer's disease (AD) pathology. However, transcriptomic analyses across fifteen mouse brain regions revealed that the cerebellum undergoes some of the earliest and most pronounced age-related changes. To investigate cerebellar aging, we applied single-nucleus RNA sequencing (RNA-seq), microglial bulk RNA-seq, and multiplexed error-robust fluorescence in situ hybridization (MERFISH)-based spatial transcriptomics. Microglia showed the most prominent changes, including elevated expression of a neuroprotective signature and reduced expression of a lipid-droplet-accumulating signature compared to hippocampal microglia. Spatial analyses further revealed that aged cerebellar microglia were positioned in close proximity to granule cells. Utilizing this relationship, we identified a proximity-dependent transcriptional state defined by the neuron-associated microglial signature. This signature reveals a region-specific microglial adaptation, highlighting cerebellar reorganization with age and potential resilience to AD.

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Research summary

The paper claims that aged cerebellar microglia exhibit a region-specific transcriptional adaptation that may contribute to resilience against Alzheimer's disease. This research is relevant as it explores cellular changes associated with aging and their potential implications for age-related diseases, contributing to the understanding of aging mechanisms.

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