Single-cell sequencing of entorhinal cortex reveals widespread disruption of neuropeptide networks in Alzheimer's disease

Manci Li; Peter A. Larsen

doi:10.1002/alz.12979

Single-cell sequencing of entorhinal cortex reveals widespread disruption of neuropeptide networks in Alzheimer's disease

Manci Li, Peter A. Larsen

Veterinary and Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

INTRODUCTION: Abnormalities of neuropeptides (NPs) that play important roles in modulating neuronal activities are commonly observed in Alzheimer's disease (AD). We hypothesize that NP network disruption is widespread in AD brains. METHODS: Single-cell transcriptomic data from the entorhinal cortex (EC) were used to investigate the NP network disruption in AD. Bulk RNA-sequencing data generated from the temporal cortex by independent groups and machine learning were employed to identify key NPs involved in AD. The relationship between aging and AD-associated NP (ADNP) expression was studied using GTEx data. RESULTS: The proportion of cells expressing NPs but not their receptors decreased significantly in AD. Neurons expressing higher level and greater diversity of NPs were disproportionately absent in AD. Increased age coincides with decreased ADNP expression in the hippocampus. DISCUSSION: NP network disruption is widespread in AD EC. Neurons expressing more NPs may be selectively vulnerable to AD. Decreased expression of NPs participates in early AD pathogenesis. We predict that the NP network can be harnessed for treatment and/or early diagnosis of AD.

Original language	English (US)
Pages (from-to)	3575-3592
Number of pages	18
Journal	Alzheimer's and Dementia
Volume	19
Issue number	8
DOIs	https://doi.org/10.1002/alz.12979
State	Published - Aug 2023

Bibliographical note

Funding Information:
Dr. Ling Li from the Department of Experimental and Clinical Pharmacology and Dr. Alice Larson from the Department of Veterinary and Biomedical Sciences at the University of Minnesota provided helpful comments that improved the quality of the research presented herein. The results published here are in part based on data obtained from the AD Knowledge Portal. These data were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by Dr. Eric Schadt from Mount Sinai School of Medicine. The Mayo RNAseq study was led by Dr. Nilüfer Ertekin-Taner, Mayo Clinic, Jacksonville, FL, as part of the multi-PI U01 AG046139 (MPIs Golde, Ertekin-Taner, Younkin, Price). Samples were provided from the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA Grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS Grant R01 NS080820, CurePSP Foundation, and support from the Mayo Foundation. Study data included samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (Contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (Contracts 4001, 0011, 05-901, and 1001 to the Arizona Parkinson's Disease Consortium), and the Michael J. Fox Foundation for Parkinson's Research. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 10/05/2022. Figures were organized in BioRender (biorender.com). Peter A. Larsen provided discretionary funds supporting ML throughout the research. Manci Li is also supported by the Doctoral Dissertation Fellowship granted through the Graduate School Fellowship Office at the University of Minnesota.

Funding Information:
Dr. Ling Li from the Department of Experimental and Clinical Pharmacology and Dr. Alice Larson from the Department of Veterinary and Biomedical Sciences at the University of Minnesota provided helpful comments that improved the quality of the research presented herein. The results published here are in part based on data obtained from the AD Knowledge Portal. These data were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by Dr. Eric Schadt from Mount Sinai School of Medicine. The Mayo RNAseq study was led by Dr. Nilüfer Ertekin‐Taner, Mayo Clinic, Jacksonville, FL, as part of the multi‐PI U01 AG046139 (MPIs Golde, Ertekin‐Taner, Younkin, Price). Samples were provided from the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA Grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS Grant R01 NS080820, CurePSP Foundation, and support from the Mayo Foundation. Study data included samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (Contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (Contracts 4001, 0011, 05‐901, and 1001 to the Arizona Parkinson's Disease Consortium), and the Michael J. Fox Foundation for Parkinson's Research. The Genotype‐Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 10/05/2022. Figures were organized in BioRender (biorender.com). Peter A. Larsen provided discretionary funds supporting ML throughout the research. Manci Li is also supported by the Doctoral Dissertation Fellowship granted through the Graduate School Fellowship Office at the University of Minnesota.

Publisher Copyright:
© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

Keywords

Alzheimer's disease
G-protein-coupled receptors
neuropeptides
RNA-seq
single-cell analysis

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/alz.12979

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@article{14763b7594dd4fcebde34f777e83c835,

title = "Single-cell sequencing of entorhinal cortex reveals widespread disruption of neuropeptide networks in Alzheimer's disease",

abstract = "INTRODUCTION: Abnormalities of neuropeptides (NPs) that play important roles in modulating neuronal activities are commonly observed in Alzheimer's disease (AD). We hypothesize that NP network disruption is widespread in AD brains. METHODS: Single-cell transcriptomic data from the entorhinal cortex (EC) were used to investigate the NP network disruption in AD. Bulk RNA-sequencing data generated from the temporal cortex by independent groups and machine learning were employed to identify key NPs involved in AD. The relationship between aging and AD-associated NP (ADNP) expression was studied using GTEx data. RESULTS: The proportion of cells expressing NPs but not their receptors decreased significantly in AD. Neurons expressing higher level and greater diversity of NPs were disproportionately absent in AD. Increased age coincides with decreased ADNP expression in the hippocampus. DISCUSSION: NP network disruption is widespread in AD EC. Neurons expressing more NPs may be selectively vulnerable to AD. Decreased expression of NPs participates in early AD pathogenesis. We predict that the NP network can be harnessed for treatment and/or early diagnosis of AD.",

keywords = "Alzheimer's disease, G-protein-coupled receptors, neuropeptides, RNA-seq, single-cell analysis",

author = "Manci Li and Larsen, {Peter A.}",

note = "Funding Information: Dr. Ling Li from the Department of Experimental and Clinical Pharmacology and Dr. Alice Larson from the Department of Veterinary and Biomedical Sciences at the University of Minnesota provided helpful comments that improved the quality of the research presented herein. The results published here are in part based on data obtained from the AD Knowledge Portal. These data were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by Dr. Eric Schadt from Mount Sinai School of Medicine. The Mayo RNAseq study was led by Dr. Nil{\"u}fer Ertekin-Taner, Mayo Clinic, Jacksonville, FL, as part of the multi-PI U01 AG046139 (MPIs Golde, Ertekin-Taner, Younkin, Price). Samples were provided from the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA Grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS Grant R01 NS080820, CurePSP Foundation, and support from the Mayo Foundation. Study data included samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (Contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (Contracts 4001, 0011, 05-901, and 1001 to the Arizona Parkinson's Disease Consortium), and the Michael J. Fox Foundation for Parkinson's Research. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 10/05/2022. Figures were organized in BioRender (biorender.com). Peter A. Larsen provided discretionary funds supporting ML throughout the research. Manci Li is also supported by the Doctoral Dissertation Fellowship granted through the Graduate School Fellowship Office at the University of Minnesota. Funding Information: Dr. Ling Li from the Department of Experimental and Clinical Pharmacology and Dr. Alice Larson from the Department of Veterinary and Biomedical Sciences at the University of Minnesota provided helpful comments that improved the quality of the research presented herein. The results published here are in part based on data obtained from the AD Knowledge Portal. These data were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by Dr. Eric Schadt from Mount Sinai School of Medicine. The Mayo RNAseq study was led by Dr. Nil{\"u}fer Ertekin‐Taner, Mayo Clinic, Jacksonville, FL, as part of the multi‐PI U01 AG046139 (MPIs Golde, Ertekin‐Taner, Younkin, Price). Samples were provided from the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA Grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS Grant R01 NS080820, CurePSP Foundation, and support from the Mayo Foundation. Study data included samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (Contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (Contracts 4001, 0011, 05‐901, and 1001 to the Arizona Parkinson's Disease Consortium), and the Michael J. Fox Foundation for Parkinson's Research. The Genotype‐Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 10/05/2022. Figures were organized in BioRender (biorender.com). Peter A. Larsen provided discretionary funds supporting ML throughout the research. Manci Li is also supported by the Doctoral Dissertation Fellowship granted through the Graduate School Fellowship Office at the University of Minnesota. Publisher Copyright: {\textcopyright} 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2023",

month = aug,

doi = "10.1002/alz.12979",

language = "English (US)",

volume = "19",

pages = "3575--3592",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "John Wiley and Sons Inc.",

number = "8",

}

TY - JOUR

T1 - Single-cell sequencing of entorhinal cortex reveals widespread disruption of neuropeptide networks in Alzheimer's disease

AU - Li, Manci

AU - Larsen, Peter A.

N1 - Funding Information: Dr. Ling Li from the Department of Experimental and Clinical Pharmacology and Dr. Alice Larson from the Department of Veterinary and Biomedical Sciences at the University of Minnesota provided helpful comments that improved the quality of the research presented herein. The results published here are in part based on data obtained from the AD Knowledge Portal. These data were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by Dr. Eric Schadt from Mount Sinai School of Medicine. The Mayo RNAseq study was led by Dr. Nilüfer Ertekin-Taner, Mayo Clinic, Jacksonville, FL, as part of the multi-PI U01 AG046139 (MPIs Golde, Ertekin-Taner, Younkin, Price). Samples were provided from the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA Grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS Grant R01 NS080820, CurePSP Foundation, and support from the Mayo Foundation. Study data included samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (Contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (Contracts 4001, 0011, 05-901, and 1001 to the Arizona Parkinson's Disease Consortium), and the Michael J. Fox Foundation for Parkinson's Research. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 10/05/2022. Figures were organized in BioRender (biorender.com). Peter A. Larsen provided discretionary funds supporting ML throughout the research. Manci Li is also supported by the Doctoral Dissertation Fellowship granted through the Graduate School Fellowship Office at the University of Minnesota. Funding Information: Dr. Ling Li from the Department of Experimental and Clinical Pharmacology and Dr. Alice Larson from the Department of Veterinary and Biomedical Sciences at the University of Minnesota provided helpful comments that improved the quality of the research presented herein. The results published here are in part based on data obtained from the AD Knowledge Portal. These data were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank and were provided by Dr. Eric Schadt from Mount Sinai School of Medicine. The Mayo RNAseq study was led by Dr. Nilüfer Ertekin‐Taner, Mayo Clinic, Jacksonville, FL, as part of the multi‐PI U01 AG046139 (MPIs Golde, Ertekin‐Taner, Younkin, Price). Samples were provided from the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA Grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS Grant R01 NS080820, CurePSP Foundation, and support from the Mayo Foundation. Study data included samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (Contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (Contracts 4001, 0011, 05‐901, and 1001 to the Arizona Parkinson's Disease Consortium), and the Michael J. Fox Foundation for Parkinson's Research. The Genotype‐Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 10/05/2022. Figures were organized in BioRender (biorender.com). Peter A. Larsen provided discretionary funds supporting ML throughout the research. Manci Li is also supported by the Doctoral Dissertation Fellowship granted through the Graduate School Fellowship Office at the University of Minnesota. Publisher Copyright: © 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

PY - 2023/8

Y1 - 2023/8

N2 - INTRODUCTION: Abnormalities of neuropeptides (NPs) that play important roles in modulating neuronal activities are commonly observed in Alzheimer's disease (AD). We hypothesize that NP network disruption is widespread in AD brains. METHODS: Single-cell transcriptomic data from the entorhinal cortex (EC) were used to investigate the NP network disruption in AD. Bulk RNA-sequencing data generated from the temporal cortex by independent groups and machine learning were employed to identify key NPs involved in AD. The relationship between aging and AD-associated NP (ADNP) expression was studied using GTEx data. RESULTS: The proportion of cells expressing NPs but not their receptors decreased significantly in AD. Neurons expressing higher level and greater diversity of NPs were disproportionately absent in AD. Increased age coincides with decreased ADNP expression in the hippocampus. DISCUSSION: NP network disruption is widespread in AD EC. Neurons expressing more NPs may be selectively vulnerable to AD. Decreased expression of NPs participates in early AD pathogenesis. We predict that the NP network can be harnessed for treatment and/or early diagnosis of AD.

AB - INTRODUCTION: Abnormalities of neuropeptides (NPs) that play important roles in modulating neuronal activities are commonly observed in Alzheimer's disease (AD). We hypothesize that NP network disruption is widespread in AD brains. METHODS: Single-cell transcriptomic data from the entorhinal cortex (EC) were used to investigate the NP network disruption in AD. Bulk RNA-sequencing data generated from the temporal cortex by independent groups and machine learning were employed to identify key NPs involved in AD. The relationship between aging and AD-associated NP (ADNP) expression was studied using GTEx data. RESULTS: The proportion of cells expressing NPs but not their receptors decreased significantly in AD. Neurons expressing higher level and greater diversity of NPs were disproportionately absent in AD. Increased age coincides with decreased ADNP expression in the hippocampus. DISCUSSION: NP network disruption is widespread in AD EC. Neurons expressing more NPs may be selectively vulnerable to AD. Decreased expression of NPs participates in early AD pathogenesis. We predict that the NP network can be harnessed for treatment and/or early diagnosis of AD.

KW - Alzheimer's disease

KW - G-protein-coupled receptors

KW - neuropeptides

KW - RNA-seq

KW - single-cell analysis

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U2 - 10.1002/alz.12979

DO - 10.1002/alz.12979

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AN - SCOPUS:85148575070

SN - 1552-5260

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EP - 3592

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 8

ER -

Single-cell sequencing of entorhinal cortex reveals widespread disruption of neuropeptide networks in Alzheimer's disease

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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