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Single-nucleus transcriptomic profiling of aging Down Syndrome brains

Down syndrome (DS) – trisomy of human chromosome 21 (HSA21) – is characterized by lifelong cognitive impairments and development of neuropathological hallmarks of Alzheimer’s disease (AD). The cellular and molecular modifications responsible for these effects are not understood. Here we performed single-nucleus RNA-sequencing (snRNA-seq) employing both short (Illumina) and long-read (Pacific Biosciences) sequencing technologies on a total of 29 DS and non-DS control prefrontal cortex samples. In DS, the ratio of inhibitory-to-excitatory neurons was significantly increased, which was not observed in previous reports examining sporadic AD. DS microglial transcriptomes displayed AD-related aging and activation signatures in advance of AD neuropathology, with increased microglial expression of C1q complement genes (associated with dendritic pruning) and the HSA21 transcription factor gene RUNX1. Long-read sequencing detected vast RNA isoform diversity within and amongst specific cell types including numerous novel sequences that differed between DS and normal brains. Notably, over 8,000 genes produced RNAs containing intra-exonic junctions (IEJs), including APP that had previously been associated with somatic gene recombination. These and related results illuminate large-scale cellular and transcriptomic alterations as novel features of the aging DS brain.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001008284 Sequel 16
EGAD00001008285 Sequel 16
EGAD00001008286 Sequel 16
EGAD00001008287 Illumina NovaSeq 6000 29
EGAD00001008288 Sequel 16
Publications Citations
Altered cell and RNA isoform diversity in aging Down syndrome brains.
Proc Natl Acad Sci U S A 118: 2021 e2114326118
Asynchronous excitatory neuron development in an isogenic cortical spheroid model of Down syndrome.
Front Neurosci 16: 2022 932384