Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment

Natalie Piehl; Lynn van Olst; Abhirami Ramakrishnan; Victoria Teregulova; Brooke Simonton; Ziyang Zhang; Emma Tapp; Divya Channappa; Hamilton Oh; Patricia M. Losada; Jarod Rutledge; Alexandra N. Trelle; Elizabeth C. Mormino; Fanny Elahi; Douglas R. Galasko; Victor W. Henderson; Anthony D. Wagner; Tony Wyss-Coray; David Gate

doi:10.1016/j.cell.2022.11.019

Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment

Natalie Piehl, Lynn van Olst, Abhirami Ramakrishnan, Victoria Teregulova, Brooke Simonton, Ziyang Zhang, Emma Tapp, Divya Channappa, Hamilton Oh, Patricia M. Losada, Jarod Rutledge, Alexandra N. Trelle, Elizabeth C. Mormino, Fanny Elahi, Douglas R. Galasko, Victor W. Henderson, Anthony D. Wagner, Tony Wyss-Coray, David Gate

Neurology

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

53 Scopus citations

Abstract

Cerebrospinal fluid (CSF) contains a tightly regulated immune system. However, knowledge is lacking about how CSF immunity is altered with aging or neurodegenerative disease. Here, we performed single-cell RNA sequencing on CSF from 45 cognitively normal subjects ranging from 54 to 82 years old. We uncovered an upregulation of lipid transport genes in monocytes with age. We then compared this cohort with 14 cognitively impaired subjects. In cognitively impaired subjects, downregulation of lipid transport genes in monocytes occurred concomitantly with altered cytokine signaling to CD8 T cells. Clonal CD8 T effector memory cells upregulated C-X-C motif chemokine receptor 6 (CXCR6) in cognitively impaired subjects. The CXCR6 ligand, C-X-C motif chemokine ligand 16 (CXCL16), was elevated in the CSF of cognitively impaired subjects, suggesting CXCL16-CXCR6 signaling as a mechanism for antigen-specific T cell entry into the brain. Cumulatively, these results reveal cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment.

Original language	English
Pages (from-to)	5028-5039.e13
Journal	Cell
Volume	185
Issue number	26
DOIs	https://doi.org/10.1016/j.cell.2022.11.019
State	Published - 22 Dec 2022

Keywords

Alzheimer's disease
T cells
adaptive immunity
aging
cerebrospinal fluid
cognitive impairment

Access to Document

10.1016/j.cell.2022.11.019

Cite this

Piehl, N., van Olst, L., Ramakrishnan, A., Teregulova, V., Simonton, B., Zhang, Z., Tapp, E., Channappa, D., Oh, H., Losada, P. M., Rutledge, J., Trelle, A. N., Mormino, E. C., Elahi, F., Galasko, D. R., Henderson, V. W., Wagner, A. D., Wyss-Coray, T., & Gate, D. (2022). Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment. Cell, 185(26), 5028-5039.e13. https://doi.org/10.1016/j.cell.2022.11.019

@article{c32fbebfec9e46a0a417d8610c3a8b0c,

title = "Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment",

abstract = "Cerebrospinal fluid (CSF) contains a tightly regulated immune system. However, knowledge is lacking about how CSF immunity is altered with aging or neurodegenerative disease. Here, we performed single-cell RNA sequencing on CSF from 45 cognitively normal subjects ranging from 54 to 82 years old. We uncovered an upregulation of lipid transport genes in monocytes with age. We then compared this cohort with 14 cognitively impaired subjects. In cognitively impaired subjects, downregulation of lipid transport genes in monocytes occurred concomitantly with altered cytokine signaling to CD8 T cells. Clonal CD8 T effector memory cells upregulated C-X-C motif chemokine receptor 6 (CXCR6) in cognitively impaired subjects. The CXCR6 ligand, C-X-C motif chemokine ligand 16 (CXCL16), was elevated in the CSF of cognitively impaired subjects, suggesting CXCL16-CXCR6 signaling as a mechanism for antigen-specific T cell entry into the brain. Cumulatively, these results reveal cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment.",

keywords = "Alzheimer's disease, T cells, adaptive immunity, aging, cerebrospinal fluid, cognitive impairment",

author = "Natalie Piehl and {van Olst}, Lynn and Abhirami Ramakrishnan and Victoria Teregulova and Brooke Simonton and Ziyang Zhang and Emma Tapp and Divya Channappa and Hamilton Oh and Losada, {Patricia M.} and Jarod Rutledge and Trelle, {Alexandra N.} and Mormino, {Elizabeth C.} and Fanny Elahi and Galasko, {Douglas R.} and Henderson, {Victor W.} and Wagner, {Anthony D.} and Tony Wyss-Coray and David Gate",

note = "Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = dec,

day = "22",

doi = "10.1016/j.cell.2022.11.019",

language = "English",

volume = "185",

pages = "5028--5039.e13",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "26",

}

Piehl, N, van Olst, L, Ramakrishnan, A, Teregulova, V, Simonton, B, Zhang, Z, Tapp, E, Channappa, D, Oh, H, Losada, PM, Rutledge, J, Trelle, AN, Mormino, EC, Elahi, F, Galasko, DR, Henderson, VW, Wagner, AD, Wyss-Coray, T & Gate, D 2022, 'Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment', Cell, vol. 185, no. 26, pp. 5028-5039.e13. https://doi.org/10.1016/j.cell.2022.11.019

TY - JOUR

T1 - Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment

AU - Piehl, Natalie

AU - van Olst, Lynn

AU - Ramakrishnan, Abhirami

AU - Teregulova, Victoria

AU - Simonton, Brooke

AU - Zhang, Ziyang

AU - Tapp, Emma

AU - Channappa, Divya

AU - Oh, Hamilton

AU - Losada, Patricia M.

AU - Rutledge, Jarod

AU - Trelle, Alexandra N.

AU - Mormino, Elizabeth C.

AU - Elahi, Fanny

AU - Galasko, Douglas R.

AU - Henderson, Victor W.

AU - Wagner, Anthony D.

AU - Wyss-Coray, Tony

AU - Gate, David

PY - 2022/12/22

Y1 - 2022/12/22

N2 - Cerebrospinal fluid (CSF) contains a tightly regulated immune system. However, knowledge is lacking about how CSF immunity is altered with aging or neurodegenerative disease. Here, we performed single-cell RNA sequencing on CSF from 45 cognitively normal subjects ranging from 54 to 82 years old. We uncovered an upregulation of lipid transport genes in monocytes with age. We then compared this cohort with 14 cognitively impaired subjects. In cognitively impaired subjects, downregulation of lipid transport genes in monocytes occurred concomitantly with altered cytokine signaling to CD8 T cells. Clonal CD8 T effector memory cells upregulated C-X-C motif chemokine receptor 6 (CXCR6) in cognitively impaired subjects. The CXCR6 ligand, C-X-C motif chemokine ligand 16 (CXCL16), was elevated in the CSF of cognitively impaired subjects, suggesting CXCL16-CXCR6 signaling as a mechanism for antigen-specific T cell entry into the brain. Cumulatively, these results reveal cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment.

AB - Cerebrospinal fluid (CSF) contains a tightly regulated immune system. However, knowledge is lacking about how CSF immunity is altered with aging or neurodegenerative disease. Here, we performed single-cell RNA sequencing on CSF from 45 cognitively normal subjects ranging from 54 to 82 years old. We uncovered an upregulation of lipid transport genes in monocytes with age. We then compared this cohort with 14 cognitively impaired subjects. In cognitively impaired subjects, downregulation of lipid transport genes in monocytes occurred concomitantly with altered cytokine signaling to CD8 T cells. Clonal CD8 T effector memory cells upregulated C-X-C motif chemokine receptor 6 (CXCR6) in cognitively impaired subjects. The CXCR6 ligand, C-X-C motif chemokine ligand 16 (CXCL16), was elevated in the CSF of cognitively impaired subjects, suggesting CXCL16-CXCR6 signaling as a mechanism for antigen-specific T cell entry into the brain. Cumulatively, these results reveal cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment.

KW - Alzheimer's disease

KW - T cells

KW - adaptive immunity

KW - aging

KW - cerebrospinal fluid

KW - cognitive impairment

UR - http://www.scopus.com/inward/record.url?scp=85144635840&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2022.11.019

DO - 10.1016/j.cell.2022.11.019

M3 - Article

C2 - 36516855

AN - SCOPUS:85144635840

SN - 0092-8674

VL - 185

SP - 5028-5039.e13

JO - Cell

JF - Cell

IS - 26

ER -

Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment

Abstract

Keywords

Access to Document

Fingerprint

Cite this