@article{586b689d02e94d57821327e3e4965b95,
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 = "Funding Information: We thank A.C. Yang (UC, San Francisco) and R.T. Vest (Qinotto Inc.) for helpful advice. We also thank the clinical staffs of the Stanford Alzheimer{\textquoteright}s Disease Research Center (ADRC) and the Stanford Brain Rejuvenation Program for their assistance acquiring patient samples. Some figures were created using BioRender.com . This work was supported by a NIA R01AG078713-01 (D.G.), a 10x Genomics Early Career Investigator Award (D.G.), a National Institute of Neurologic Disease and Stroke K99/R00 Pathway to Independence award NS112458-01A1 (D.G.), an Irene Diamond Fund/AFAR Postdoctoral Transition Award in Aging (D.G.), the Cure Alzheimer's Fund (D.G.), the Alzheimer's Association ADSF-21-818117 (D.G. and T.W.-C.), the NOMIS Foundation (T.W.-C.), NIA R01AG045034 05 (T.W.-C.), the NIA funded Stanford ADRC P50AG047366 and P30AG066515 (V.W.H.), R01AG048076 (A.D.W.), UC San Diego Shiley-Marcos ADRC P30 AG062429 (D.R.G.), and a pilot project through the Northwestern University ADRC 1P30AG072977-01 (D.G.). Funding Information: We thank A.C. Yang (UC, San Francisco) and R.T. Vest (Qinotto Inc.) for helpful advice. We also thank the clinical staffs of the Stanford Alzheimer's Disease Research Center (ADRC) and the Stanford Brain Rejuvenation Program for their assistance acquiring patient samples. Some figures were created using BioRender.com. This work was supported by a NIA R01AG078713-01 (D.G.), a 10x Genomics Early Career Investigator Award (D.G.), a National Institute of Neurologic Disease and Stroke K99/R00 Pathway to Independence award NS112458-01A1 (D.G.), an Irene Diamond Fund/AFAR Postdoctoral Transition Award in Aging (D.G.), the Cure Alzheimer's Fund (D.G.), the Alzheimer's Association ADSF-21-818117 (D.G. and T.W.-C.), the NOMIS Foundation (T.W.-C.), NIA R01AG045034 05 (T.W.-C.), the NIA funded Stanford ADRC P50AG047366 and P30AG066515 (V.W.H.), R01AG048076 (A.D.W.), UC San Diego Shiley-Marcos ADRC P30 AG062429 (D.R.G.), and a pilot project through the Northwestern University ADRC 1P30AG072977-01 (D.G.). N.P. performed bioinformatics analysis and generated figures. L.v.O. directed experiments, edited figures, and conducted confocal imaging. A.R. V.T. B.S. Z.Z. E.T. and D.C. assisted with sample processing. E.T. and D.G. performed cell sorting and library preparation. H.O. P.M.L. and J.R. assisted with CSF protein measurements and analysis. F.E. D.R.G. A.N.T. E.C.M. V.W.H. and A.D.W. provided patient samples. T.W.-C. provided reagents. D.G. conceptualized and led the study and wrote the manuscript. All authors read and approved the final manuscript. T.W.-C. and D.G. are co-inventors on a patent related to this work. Patent US-2022-0170908-A1 is for compositions and methods for measuring T cell markers associated with AD. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = dec,
day = "22",
doi = "10.1016/j.cell.2022.11.019",
language = "English (US)",
volume = "185",
pages = "5028--5039.e13",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "26",
}