Analysis of microisolated frontal cortex excitatory layer III and V pyramidal neurons reveals a neurodegenerative phenotype in individuals with Down syndrome.
Alzheimer’s disease
Bioinformatics
Down syndrome
Frontal cortex
Laser capture microdissection
RNA sequencing
Selective vulnerability
Trisomy
Journal
Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041
Informations de publication
Date de publication:
06 Aug 2024
06 Aug 2024
Historique:
received:
04
03
2024
accepted:
13
07
2024
revised:
12
07
2024
medline:
6
8
2024
pubmed:
6
8
2024
entrez:
6
8
2024
Statut:
epublish
Résumé
We elucidated the molecular fingerprint of vulnerable excitatory neurons within select cortical lamina of individuals with Down syndrome (DS) for mechanistic understanding and therapeutic potential that also informs Alzheimer's disease (AD) pathophysiology. Frontal cortex (BA9) layer III (L3) and layer V (L5) pyramidal neurons were microisolated from postmortem human DS and age- and sex-matched controls (CTR) to interrogate differentially expressed genes (DEGs) and key biological pathways relevant to neurodegenerative programs. We identified > 2300 DEGs exhibiting convergent dysregulation of gene expression in both L3 and L5 pyramidal neurons in individuals with DS versus CTR subjects. DEGs included over 100 triplicated human chromosome 21 genes in L3 and L5 neurons, demonstrating a trisomic neuronal karyotype in both laminae. In addition, thousands of other DEGs were identified, indicating gene dysregulation is not limited to trisomic genes in the aged DS brain, which we postulate is relevant to AD pathobiology. Convergent L3 and L5 DEGs highlighted pertinent biological pathways and identified key pathway-associated targets likely underlying corticocortical neurodegeneration and related cognitive decline in individuals with DS. Select key DEGs were interrogated as potential hub genes driving dysregulation, namely the triplicated DEGs amyloid precursor protein (APP) and superoxide dismutase 1 (SOD1), along with key signaling DEGs including mitogen activated protein kinase 1 and 3 (MAPK1, MAPK3) and calcium calmodulin dependent protein kinase II alpha (CAMK2A), among others. Hub DEGs determined from multiple pathway analyses identified potential therapeutic candidates for amelioration of cortical neuron dysfunction and cognitive decline in DS with translational relevance to AD.
Identifiants
pubmed: 39105932
doi: 10.1007/s00401-024-02768-0
pii: 10.1007/s00401-024-02768-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
16Subventions
Organisme : NIA NIH HHS
ID : AG014449
Pays : United States
Organisme : NIA NIH HHS
ID : AG017617
Pays : United States
Organisme : NIA NIH HHS
ID : AG072599
Pays : United States
Organisme : NIA NIH HHS
ID : AG074004
Pays : United States
Organisme : NIA NIH HHS
ID : AG077103
Pays : United States
Organisme : NIA NIH HHS
ID : AG085572
Pays : United States
Organisme : NIA NIH HHS
ID : AG081286
Pays : United States
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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