Molecular Signatures of Resilience to Alzheimer’s Disease in Neocortical Layer 4 Neurons

Cite

Dharshini, S.A.P., Sanz-Ros, J., Pan, J., Tang, W., Vallejo, K., Otero-Garcia, M. and Cobos, I., 2024. Molecular Signatures of Resilience to Alzheimer's Disease in Neocortical Layer 4 Neurons. bioRxiv, pp.2024-11. https://doi.org/10.1101/2024.11.03.621787

Abstract

Single-cell omics is advancing our understanding of selective neuronal vulnerability in Alzheimer’s disease (AD), revealing specific subtypes that are either susceptible or resilient to neurodegeneration. Using single-nucleus and spatial transcriptomics to compare neocortical regions affected early (prefrontal cortex and precuneus) or late (primary visual cortex) in AD, we identified a resilient excitatory population in layer 4 of the primary visual cortex expressing RORB, CUX2, and EYA4. Layer 4 neurons in association neocortex also remained relatively preserved as AD progressed and shared overlapping molecular signatures of resilience. Early in the disease, resilient neurons upregulated genes associated with synapse maintenance, synaptic plasticity, calcium homeostasis, and neuroprotective factors, including GRIN2A, RORA, NRXN1, NLGN1, NCAM2, FGF14, NRG3, NEGR1, and CSMD1. We also identified KCNIP4, which encodes a voltage-gated potassium (Kv) channel-interacting protein that interacts with Kv4.2 channels and presenilins, as a key factor linked to resilience. KCNIP4 was consistently upregulated in the early stages of pathology. Furthermore, AAV-mediated overexpression of Kcnip4 in a humanized AD mouse model reduced the expression of the activity-dependent genes Arc and c-Fos, suggesting compensatory mechanisms against neuronal hyperexcitability. Our dataset provides a valuable resource for investigating mechanisms underlying resilience to neurodegeneration.

Datasets

1. All cells

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APOE class
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Braak stage
Disease group
Amyloid
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Race
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RNA integrity number
Subject ID
Age group
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Major cell type
Cell type
NP diagonis
Assay
Disease
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Sample preservation method
Leiden clustering
L4 clusters across brain region
E3/E3250591 cells
E3/E4128408 cells
E4/E428782 cells
E2/E416487 cells
Unassigned260 cells
Molecular Signatures of Resilience to Alzheimer’s Disease in Neocortical Layer 4 Neurons

2. Excitatory

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APOE class
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Braak stage
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Amyloid
Postmortem interval (hours)
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Age group
Postmortem interval group
RNA integrity number group
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NP diagonis
Assay
Disease
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Leiden clustering
L4 clusters across brain region
E3/E3169021 cells
E3/E486145 cells
E4/E417251 cells
E2/E410280 cells
Unassigned233 cells
Molecular Signatures of Resilience to Alzheimer’s Disease in Neocortical Layer 4 Neurons

3. Inhibitory

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APOE class
Brain region
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Braak stage
Disease group
Amyloid
Postmortem interval (hours)
Race
Age (years)
RNA integrity number
Age group
Postmortem interval group
RNA integrity number group
Major cell type
Cell type
NP diagonis
Assay
Disease
Sex
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Ethnicity
Sample preservation method
Leiden clustering
E3/E346930 cells
E3/E423237 cells
E4/E45886 cells
E2/E43214 cells
Unassigned27 cells
Molecular Signatures of Resilience to Alzheimer’s Disease in Neocortical Layer 4 Neurons

Alias names

GSE263468