Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer's disease.
Neuron
; 110(18): 2929-2948.e8, 2022 09 21.
Article
em En
| MEDLINE
| ID: mdl-35882228
ABSTRACT
Tau aggregation in neurofibrillary tangles (NFTs) is closely associated with neurodegeneration and cognitive decline in Alzheimer's disease (AD). However, the molecular signatures that distinguish between aggregation-prone and aggregation-resistant cell states are unknown. We developed methods for the high-throughput isolation and transcriptome profiling of single somas with NFTs from the human AD brain, quantified the susceptibility of 20 neocortical subtypes for NFT formation and death, and identified both shared and cell-type-specific signatures. NFT-bearing neurons shared a marked upregulation of synaptic transmission-related genes, including a core set of 63 genes enriched for synaptic vesicle cycling. Oxidative phosphorylation and mitochondrial dysfunction were highly cell-type dependent. Apoptosis was only modestly enriched, and the susceptibilities of NFT-bearing and NFT-free neurons for death were highly similar. Our analysis suggests that NFTs represent cell-type-specific responses to stress and synaptic dysfunction. We provide a resource for biomarker discovery and the investigation of tau-dependent and tau-independent mechanisms of neurodegeneration.
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Base de dados:
MEDLINE
Assunto principal:
Emaranhados Neurofibrilares
/
Doença de Alzheimer
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos