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Written by | Chunxiao
The mammalian brain has a limited ability to regenerate, and throughout the life cycle, a variety of brain cells such as neurons and non-neuronal cells including oligodendrocytes, microglia, astrocytes, etc.
faithfully perform their complex functions, and functional damage accumulates over a long period of time, resulting in an increasing
prevalence of neurodegenerative diseases associated with aging with age.
One of the important hypotheses of brain aging is that the homeostatic environment of brain tissue is disrupted, and neuronal and synaptic functions associated with age and neuropathy change, triggering inflammatory activation
of non-neuronal cells.
Recent transcriptomics studies also support this view
.
It also raises questions: How do molecular markers and spatial organization of different cell types and cell states change with age? How do these changes relate to aging-induced inflammatory activation? How are activated cells spatially distributed? Does this activation depend on environmental factors and cell-to-cell communication? How does aging-induced inflammation relate to systemic inflammatory responses? Answering these questions is challenging because the diversity of brain cells and the complexity of molecular organization hinder our comprehensive understanding of changes in the brain's structural systems, limiting our ability to unravel
the underlying mechanisms underlying brain function decline during aging.
On December 28, 2022, William Allen, Catherine Dulac and Xiaowei Zhuang from Harvard University published a report in the journal Cell entitled Molecular and spatial signatures of mouse brain aging at single-cell Resolution's Resource article, which characterizes cell spatial and cell type-specific changes through single-cell transcription composition and sequencing systems in senescent mouse brains, reveals aging-related changes in neuronal and non-neuronal cells, and reveals molecular and spatial features
of glial and immune cell activation during aging.
The authors first used mononuclear RNA sequencing (snRNAseq) to characterize the single-cell transcription profiles of the frontal cortex and striatum in 1-month-old and 21-month-old mice, and performed spatially resolved single-cell transcriptome detection by MERFISH, which yielded 212 cell type markers and 204 aging-related genes Using the Harmony algorithm [1], MERFISH and snRNA-seq data were co-embedded and comprehensively clustered to generate a total of 43 neuronal and non-neuronal cell types (Figure 1).
Figure 1: Spatially resolved single-cell transcriptome analysis of the frontal cortex and striatum of mice Next, the authors analyzed changes in cell composition and status in each brain region based on MERFISH data.
Neuronal clusters did not show any significant changes in abundance, and in the senescent group, the abundance of oligodendrocytes increased, while the abundance of oligodendrocytes precursor cells decreased significantly, and oligodendrocytes were inflammatorily activated
.
Microglia, endothelial cells, and astrocytes also exhibit age-dependent population variations, including inflammatory activation and T cell infiltration
.
In order to visualize the spatial organization of cells as a whole, the authors performed hierarchical clustering according to the composition of cells in their spatial neighborhood, and the resulting spatial clustering naturally segmented the imaging area into known anatomical structures, including the pia mater, cortical layer, corpus callosum, striatum, ventricles, and subcortical olfactory area
。 As expected, different excitatory clusters are distributed in layers in the cortex, for example, midspinous neurons are localized to the striatum, oligodendrocytes are enriched in the corpus callosum, while oligodendrocytes precursors, astrocytes, microglia, and endothelial cells are distributed essentially evenly throughout the imaging area, and the astrocytes status in the corpus callosum changes
with animal aging.
Based on snRNA-seq data, the authors also determined the number of
genes that were differentially expressed in individual neuronal and non-neuronal cell types in juvenile and senescent animals.
Non-neuronal cells tend to exhibit more age-dependent differentially expressed genes than neurons, many age-dependent genes are expressed differently in a cell type-specific manner, and genes that are upregulated with age in neurons (especially suppressor neurons) are enriched in pathways related to neurodegenerative diseases, oxidative responses, and mitochondrial function, while genes that upregulate with age in non-neuronal cells tend to be associated with inflammatory and immune responses
。 GO and KEGG enrichment analysis showed that genes upregulated with age in neurons (especially suppressor neurons) were enriched in pathways associated with neurodegenerative diseases, oxidative responses, and mitochondrial function, while genes upregulated with age in non-neuronal cells were mainly associated with
inflammatory and immune responses.
Many genes that are upregulated by aging exhibit specific spatial patterns, especially oligodendrocytes, astrocytes, and microglia, and the largest number of genes expressed with age in the corpus callosum white matter relative to other anatomical regions
.
At the same time, callosum white matter is a hot spot
for the activation of aging-related glial cells and immune cells.
Astrocytes and microglia activate with age and are associated with brain inflammation, so the authors thought of an interesting question: Is this encephalitis the same thing as systemic inflammation
.
LPS is a model of encephalitis that does not cross the blood-brain barrier [2], but it causes cytokines and chemokines released by peripheral immune cells to activate brain microglia and astrocytes, and the authors compared MERFISH results in mice in the untreated group and LPS-treated group and found that the composition of cell types and the organization of the overall space were highly similar.
The similarity lies in the activation of astrocytes and their enrichment at the cerebrospinal fluid-brain barrier, with the difference that aging uniquely induces microglial activation
.
Aging and LPS-induced brain inflammation are both similar and different
.
Figure 2: Molecular and spatial characteristics of mouse brain aging at single-cell resolution In summary, the authors systematically demonstrated the molecular characteristics and spatial organization
of mouse frontal cortex and striatal brain cells using spatially resolved single-cell transcriptomics during aging
.
By integrating snRNAseq and MERFISH data, a spatially resolved map of senescent brain cells was generated with genome-wide expression profiles
associated with each cell.
Changes in cell state, gene expression, and spatial organization were observed to be much more pronounced in non-neuronal cells than neurons
.
Molecular and spatial signatures of glial and immune cell activation during aging are revealed, and these results provide important insights
into the study of aging-related brain function decline and inflammation.
Original link:
https://doi.
org/10.
1016/j.
cell.
2022.
12.
010
Platemaker: Eleven
References
1.
Korsunsky, I.
, et al.
(2019).
Fast, sensitive and accurate integration of single-cell data with harmony.
Nat.
Methods 16, 1289–1296.
2.
Batista, C.
R.
A.
, et al.
(2019).
Lipopolysaccharide-induced neuroinflammation as a bridge to understand neurodegeneration.
Int.
J.
Mol.
Sci.
20, 2293
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