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Basic Science and Pathogenesis.

Zheng Yin1,2,3, Ling Teng1,2,3, Ya Zhang4

  • 1Mass General Brigham, Boston, MA, USA.

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This study reveals the cellular landscape of the aging human amygdala, identifying abundant Alzheimer's disease-associated microglia. This suggests glial cell composition may contribute to the amygdala's vulnerability in neurodegenerative diseases.

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Area of Science:

  • Neuroscience
  • Genomics
  • Cell Biology

Background:

  • The amygdala plays a crucial role in early neurodegenerative diseases like Alzheimer's disease (AD), limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and Lewy body disease (LBD).
  • The cellular architecture of the aging human amygdala remains poorly understood, hindering our comprehension of its role in neurodegeneration.

Purpose of the Study:

  • To characterize the single-cell architecture of the aging human amygdala using multi-omic single-nucleus sequencing.
  • To identify distinct cell types, cell states, and their associated molecular markers within the amygdala.

Main Methods:

  • Dissection of the basolateral amygdala from nine brain donors with varying neurodegenerative pathologies.
  • Generation of 10x single-nucleus multi-omic data (RNA and ATAC-seq) and integration using Harmony and Weighted Nearest Neighbor (WNN) algorithms.
  • Identification and visualization of cell clusters and states using Uniform Manifold Approximation and Projection (UMAP).

Main Results:

  • Successfully generated 31,662 high-quality single-nucleus multi-omes from the amygdala.
  • Identified distinct clusters for astrocytes, excitatory and inhibitory neurons, microglia, oligodendrocytes, oligodendrocyte progenitor cells, and T cells, with multiple cell states within each type.
  • Observed a high proportion of Alzheimer's disease-associated microglia (ADAM) states, expressing APOE and TREM2, significantly higher than in the frontal cortex of AD patients.

Conclusions:

  • Demonstrated the feasibility of large-scale single-cell multi-omic data generation from the human amygdala.
  • The amygdala exhibits abundant Alzheimer's disease-associated microglia, suggesting that glial cell composition may underlie its regional vulnerability in neurodegenerative disorders.