Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer’s disease
Marcos Otero-Garcia, Sameehan U. Mahajani, Debia Wakhloo, Weijing Tang, Yue-Qiang Xue, Samuel Morabito, Jie Pan, Jane Oberhauser, Angela E. Madira, Tamara Shakouri, Yongning Deng, Thomas Allison, Zihuai He, William E. Lowry, Riki Kawaguchi, Vivek Swarup, Inma Cobos
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.
Datasets
1. Single-soma transcriptomics of tangle-bearing neurons in Alzheimer’s disease - Excitatory
Metadata
SORT
Amyloid
Age
RIN
PMI
Braak
Sample.ID
Cell.Types
tissue_ontology_term_id
assay_ontology_term_id
disease_ontology_term_id
cell_type_ontology_term_id
development_stage_ontology_term_id
self_reported_ethnicity_ontology_term_id
sex_ontology_term_id
organism_ontology_term_id
donor_id
suspension_type
tissue_type
cell_type
assay
disease
organism
sex
tissue
self_reported_ethnicity
development_stage
Ex02_CUX2-COL5A2 (L2-L4)20571 cells Ex01_CUX2-LAMP5 (L2-L3)17995 cells Ex07_RORB-PCP4 (L5)14194 cells Ex10_THEMIS (L5-6)11035 cells Ex04_RORB-GABRG1 (L4-L5)7016 cells Ex03_RORB-MME (L4-L5)6468 cells Ex13_FEZF2-SEMA3D (L6b)5060 cells Ex06_RORB-PCP4-RPRM (L5)4023 cells Ex08_FEZF2-PCP4-ROBO3 (L5)2932 cells Ex05_RORB-ADGRLA (L5)2657 cells Ex12_FEZF2-SYT6 (L6)1978 cells Ex11_THEMIS-NTNG2 (L6)1666 cells Ex09_FEZF2-ADRA1A (L5b)534 cells UBERON:000045196129 cells HsapDv:000016113070 cells HANCESTRO:000511204 cells HANCESTRO:056810580 cells NCBITaxon:960696129 cells Alzheimer disease50059 cells prefrontal cortex96129 cells African American10580 cells Hispanic or Latin American5185 cells 67-year-old human stage13070 cells 81-year-old human stage9246 cells 89-year-old human stage8648 cells 80 year-old and over human stage7574 cells 62-year-old human stage7417 cells 79-year-old human stage6969 cells 68-year-old human stage6285 cells 57-year-old human stage6154 cells 72-year-old human stage5632 cells 87-year-old human stage5616 cells 66-year-old human stage5572 cells 71-year-old human stage5185 cells 61-year-old human stage4710 cells 73-year-old human stage4051 cells 2. Single-soma transcriptomics of tangle-bearing neurons in Alzheimer’s disease - Inhibitory
Metadata
SORT
Amyloid
Age
RIN
PMI
Braak
Sample.ID
Cell.Types
tissue_ontology_term_id
assay_ontology_term_id
disease_ontology_term_id
cell_type_ontology_term_id
development_stage_ontology_term_id
self_reported_ethnicity_ontology_term_id
sex_ontology_term_id
organism_ontology_term_id
donor_id
suspension_type
tissue_type
cell_type
assay
disease
organism
sex
tissue
self_reported_ethnicity
development_stage
In7_ADARB2-CALB26445 cells In6_ADARB2-LAMP52500 cells In5_LHX6-ADARB2-LAMP51414 cells In2_LHX6-PVALB-Chandelier861 cells In4_LHX6-SST-NPY194 cells UBERON:000045123197 cells NCBITaxon:960623197 cells inhibitory interneuron23197 cells Alzheimer disease11733 cells prefrontal cortex23197 cells African American2378 cells Hispanic or Latin American1254 cells 81-year-old human stage2564 cells 61-year-old human stage2429 cells 62-year-old human stage2183 cells 79-year-old human stage2172 cells 72-year-old human stage2097 cells 66-year-old human stage1899 cells 67-year-old human stage1769 cells 57-year-old human stage1608 cells 73-year-old human stage1440 cells 71-year-old human stage1254 cells 80 year-old and over human stage1061 cells 87-year-old human stage1056 cells 68-year-old human stage960 cells 89-year-old human stage705 cells Analyze this study
Source data
https://cellxgene.cziscience.com/collections/b953c942-f5d8-434f-9da7-e726ba7c1481
Alias names
GSE129308, PMID35882228, PMC9509477
Cite this study
Otero-Garcia, M., Mahajani, S.U., Wakhloo, D., Tang, W., Xue, Y.Q., Morabito, S., Pan, J., Oberhauser, J., Madira, A.E., Shakouri, T. and Deng, Y., 2022. Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer’s disease. Neuron, 110(18), pp.2929-2948. https://doi.org/10.1016/j.neuron.2022.06.021
