Distinct cytokine profiles in human brains resilient to Alzheimer's pathology

Isabel Barroeta-Espar; Laura D. Weinstock; Beatriz G. Perez-Nievas; Avery C. Meltzer; Michael Siao Tick Chong; Ana C. Amaral; Melissa E. Murray; Krista L. Moulder; John C. Morris; Nigel J. Cairns; Joseph E. Parisi; Val J. Lowe; Ronald C. Petersen; Julia Kofler; Milos D. Ikonomovic; Oscar López; William E. Klunk; Richard P. Mayeux; Matthew P. Frosch; Levi B. Wood; Teresa Gomez-Isla

doi:10.1016/j.nbd.2018.10.009

Distinct cytokine profiles in human brains resilient to Alzheimer's pathology

Isabel Barroeta-Espar, Laura D. Weinstock, Beatriz G. Perez-Nievas, Avery C. Meltzer, Michael Siao Tick Chong, Ana C. Amaral, Melissa E. Murray, Krista L. Moulder, John C. Morris, Nigel J. Cairns, Joseph E. Parisi, Val J. Lowe, Ronald C. Petersen, Julia Kofler, Milos D. Ikonomovic, Oscar López, William E. Klunk, Richard P. Mayeux, Matthew P. Frosch, Levi B. Wood^*Teresa Gomez-Isla

^*Corresponding author for this work

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

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Abstract

Our group has previously studied the brains of some unique individuals who are able to tolerate robust amounts of Alzheimer's pathological lesions (amyloid plaques and neurofibrillary tangles) without experiencing dementia while alive. These rare resilient cases do not demonstrate the patterns of neuronal/synaptic loss that are normally found in the brains of typical demented Alzheimer's patients. Moreover, they exhibit decreased astrocyte and microglial activation markers GFAP and CD68, suggesting that a suppressed neuroinflammatory response may be implicated in human brain resilience to Alzheimer's pathology. In the present work, we used a multiplexed immunoassay to profile a panel of 27 cytokines in the brains of controls, typical demented Alzheimer's cases, and two groups of resilient cases, which possessed pathology consistent with either high probability (HP, Braak stage V-VI and CERAD 2–3) or intermediate probability (IP, Braak state III-IV and CERAD 1–3) of Alzheimer's disease in the absence of dementia. We used a multivariate partial least squares regression approach to study differences in cytokine expression between resilient cases and both Alzheimer's and control cases. Our analysis identified distinct profiles of cytokines in the entorhinal cortex (one of the earliest and most severely affected brain regions in Alzheimer's disease) that are up-regulated in both HP and IP resilient cases relative to Alzheimer's and control cases. These cytokines, including IL-1β, IL-6, IL-13, and IL-4 in HP resilient cases and IL-6, IL-10, and IP-10 in IP resilient cases, delineate differential inflammatory activity in brains resilient to Alzheimer's pathology compared to Alzheimer's cases. Of note, these cytokines all have been associated with pathogen clearance and/or the resolution of inflammation. Moreover, our analysis in the superior temporal sulcus (a multimodal association cortex that consistently accumulates Alzheimer's pathology at later stages of the disease along with overt symptoms of dementia) revealed increased expression of neurotrophic factors, such as PDGF-bb and basic FGF in resilient compared to AD cases. The same region also had reduced expression of chemokines associated with microglial recruitment, including MCP-1 in HP resilient cases and MIP-1α in IP resilient cases compared to AD. Altogether, our data suggest that different patterns of cytokine expression exist in the brains of resilient and Alzheimer's cases, link these differences to reduced glial activation, increased neuronal survival and preserved cognition in resilient cases, and reveal specific cytokine targets that may prove relevant to the identification of novel mechanisms of brain resiliency to Alzheimer's pathology.

Original language	English
Pages (from-to)	327-337
Number of pages	11
Journal	Neurobiology of Disease
Volume	121
DOIs	https://doi.org/10.1016/j.nbd.2018.10.009
Publication status	Published - Jan 2019

Keywords

Alzheimer's disease
Neuroinflammation
Partial least squares regression
Resilience

UN SDGs

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

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10.1016/j.nbd.2018.10.009

Cite this

Barroeta-Espar, I., Weinstock, L. D., Perez-Nievas, B. G., Meltzer, A. C., Siao Tick Chong, M., Amaral, A. C., Murray, M. E., Moulder, K. L., Morris, J. C., Cairns, N. J., Parisi, J. E., Lowe, V. J., Petersen, R. C., Kofler, J., Ikonomovic, M. D., López, O., Klunk, W. E., Mayeux, R. P., Frosch, M. P., ... Gomez-Isla, T. (2019). Distinct cytokine profiles in human brains resilient to Alzheimer's pathology. Neurobiology of Disease, 121, 327-337. https://doi.org/10.1016/j.nbd.2018.10.009

@article{f351703db7654786b461624698a2f79f,

title = "Distinct cytokine profiles in human brains resilient to Alzheimer's pathology",

abstract = "Our group has previously studied the brains of some unique individuals who are able to tolerate robust amounts of Alzheimer's pathological lesions (amyloid plaques and neurofibrillary tangles) without experiencing dementia while alive. These rare resilient cases do not demonstrate the patterns of neuronal/synaptic loss that are normally found in the brains of typical demented Alzheimer's patients. Moreover, they exhibit decreased astrocyte and microglial activation markers GFAP and CD68, suggesting that a suppressed neuroinflammatory response may be implicated in human brain resilience to Alzheimer's pathology. In the present work, we used a multiplexed immunoassay to profile a panel of 27 cytokines in the brains of controls, typical demented Alzheimer's cases, and two groups of resilient cases, which possessed pathology consistent with either high probability (HP, Braak stage V-VI and CERAD 2–3) or intermediate probability (IP, Braak state III-IV and CERAD 1–3) of Alzheimer's disease in the absence of dementia. We used a multivariate partial least squares regression approach to study differences in cytokine expression between resilient cases and both Alzheimer's and control cases. Our analysis identified distinct profiles of cytokines in the entorhinal cortex (one of the earliest and most severely affected brain regions in Alzheimer's disease) that are up-regulated in both HP and IP resilient cases relative to Alzheimer's and control cases. These cytokines, including IL-1β, IL-6, IL-13, and IL-4 in HP resilient cases and IL-6, IL-10, and IP-10 in IP resilient cases, delineate differential inflammatory activity in brains resilient to Alzheimer's pathology compared to Alzheimer's cases. Of note, these cytokines all have been associated with pathogen clearance and/or the resolution of inflammation. Moreover, our analysis in the superior temporal sulcus (a multimodal association cortex that consistently accumulates Alzheimer's pathology at later stages of the disease along with overt symptoms of dementia) revealed increased expression of neurotrophic factors, such as PDGF-bb and basic FGF in resilient compared to AD cases. The same region also had reduced expression of chemokines associated with microglial recruitment, including MCP-1 in HP resilient cases and MIP-1α in IP resilient cases compared to AD. Altogether, our data suggest that different patterns of cytokine expression exist in the brains of resilient and Alzheimer's cases, link these differences to reduced glial activation, increased neuronal survival and preserved cognition in resilient cases, and reveal specific cytokine targets that may prove relevant to the identification of novel mechanisms of brain resiliency to Alzheimer's pathology.",

keywords = "Alzheimer's disease, Neuroinflammation, Partial least squares regression, Resilience",

author = "Isabel Barroeta-Espar and Weinstock, {Laura D.} and Perez-Nievas, {Beatriz G.} and Meltzer, {Avery C.} and {Siao Tick Chong}, Michael and Amaral, {Ana C.} and Murray, {Melissa E.} and Moulder, {Krista L.} and Morris, {John C.} and Cairns, {Nigel J.} and Parisi, {Joseph E.} and Lowe, {Val J.} and Petersen, {Ronald C.} and Julia Kofler and Ikonomovic, {Milos D.} and Oscar L{\'o}pez and Klunk, {William E.} and Mayeux, {Richard P.} and Frosch, {Matthew P.} and Wood, {Levi B.} and Teresa Gomez-Isla",

note = "Funding Information: This study was funded in part by the National Institutes of Health through grants numbers U01AG016976 and R01AG043511 (T.G.I.), P50 AG005134, P01 AG03991, P50 AG05681, P01 AG026276, UF1 AG032438 (J.C.M.), P50 AG005133 (University of Pittsburg ADRC), P01 AG025204 (W.E.K.), P50 AG016574 ( Mayo Clinic ADRC), U01 AG006786 (Mayo Clinic Study of Aging), the Cure Alzheimer's Fund, and by startup funds from the George W. Woodruff School of Mechanical Engineering at the Georgia Institute of Technology (L.B·W). L.D.W. was supported in part by the Cell and Tissue Engineering NIH Biotechnology Training Grant (T32-GM008433). Sample and data collection and sharing for this project was supported in part by the Washington Heights-Inwood Columbia Aging Project (WHICAP, P01AG07232, R01AG037212, RF1AG054023), by the National Institute on Aging (NIA) and by the National Center for Advancing Translational Sciences , National Institutes of Health , through Grant Number UL1TR001873. This manuscript has been reviewed by WHICAP investigators for scientific content and consistency of data interpretation with previous WHICAP Study publications. Funding Information: Dr. Gomez-Isla has participated as speaker in an Eli Lilly sponsored educational symposium and serves as member of an Eli Lilly Data Monitoring Committee (DMC). Dr. Lowe consults for Bayer Schering Pharma, Piramal Life Sciences and Merck Research and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals and the NIH (NIA, NCI). Dr. Morris has participated in Eli Lilly and Biogen sponsored trials. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.",

year = "2019",

month = jan,

doi = "10.1016/j.nbd.2018.10.009",

language = "English",

volume = "121",

pages = "327--337",

journal = "Neurobiology of Disease",

issn = "0969-9961",

publisher = "Elsevier",

}

Barroeta-Espar, I, Weinstock, LD, Perez-Nievas, BG, Meltzer, AC, Siao Tick Chong, M, Amaral, AC, Murray, ME, Moulder, KL, Morris, JC, Cairns, NJ, Parisi, JE, Lowe, VJ, Petersen, RC, Kofler, J, Ikonomovic, MD, López, O, Klunk, WE, Mayeux, RP, Frosch, MP, Wood, LB & Gomez-Isla, T 2019, 'Distinct cytokine profiles in human brains resilient to Alzheimer's pathology', Neurobiology of Disease, vol. 121, pp. 327-337. https://doi.org/10.1016/j.nbd.2018.10.009

TY - JOUR

T1 - Distinct cytokine profiles in human brains resilient to Alzheimer's pathology

AU - Barroeta-Espar, Isabel

AU - Weinstock, Laura D.

AU - Perez-Nievas, Beatriz G.

AU - Meltzer, Avery C.

AU - Siao Tick Chong, Michael

AU - Amaral, Ana C.

AU - Murray, Melissa E.

AU - Moulder, Krista L.

AU - Morris, John C.

AU - Cairns, Nigel J.

AU - Parisi, Joseph E.

AU - Lowe, Val J.

AU - Petersen, Ronald C.

AU - Kofler, Julia

AU - Ikonomovic, Milos D.

AU - López, Oscar

AU - Klunk, William E.

AU - Mayeux, Richard P.

AU - Frosch, Matthew P.

AU - Wood, Levi B.

AU - Gomez-Isla, Teresa

N1 - Funding Information: This study was funded in part by the National Institutes of Health through grants numbers U01AG016976 and R01AG043511 (T.G.I.), P50 AG005134, P01 AG03991, P50 AG05681, P01 AG026276, UF1 AG032438 (J.C.M.), P50 AG005133 (University of Pittsburg ADRC), P01 AG025204 (W.E.K.), P50 AG016574 ( Mayo Clinic ADRC), U01 AG006786 (Mayo Clinic Study of Aging), the Cure Alzheimer's Fund, and by startup funds from the George W. Woodruff School of Mechanical Engineering at the Georgia Institute of Technology (L.B·W). L.D.W. was supported in part by the Cell and Tissue Engineering NIH Biotechnology Training Grant (T32-GM008433). Sample and data collection and sharing for this project was supported in part by the Washington Heights-Inwood Columbia Aging Project (WHICAP, P01AG07232, R01AG037212, RF1AG054023), by the National Institute on Aging (NIA) and by the National Center for Advancing Translational Sciences , National Institutes of Health , through Grant Number UL1TR001873. This manuscript has been reviewed by WHICAP investigators for scientific content and consistency of data interpretation with previous WHICAP Study publications. Funding Information: Dr. Gomez-Isla has participated as speaker in an Eli Lilly sponsored educational symposium and serves as member of an Eli Lilly Data Monitoring Committee (DMC). Dr. Lowe consults for Bayer Schering Pharma, Piramal Life Sciences and Merck Research and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals and the NIH (NIA, NCI). Dr. Morris has participated in Eli Lilly and Biogen sponsored trials. Publisher Copyright: © 2018 Elsevier Inc. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.

PY - 2019/1

Y1 - 2019/1

N2 - Our group has previously studied the brains of some unique individuals who are able to tolerate robust amounts of Alzheimer's pathological lesions (amyloid plaques and neurofibrillary tangles) without experiencing dementia while alive. These rare resilient cases do not demonstrate the patterns of neuronal/synaptic loss that are normally found in the brains of typical demented Alzheimer's patients. Moreover, they exhibit decreased astrocyte and microglial activation markers GFAP and CD68, suggesting that a suppressed neuroinflammatory response may be implicated in human brain resilience to Alzheimer's pathology. In the present work, we used a multiplexed immunoassay to profile a panel of 27 cytokines in the brains of controls, typical demented Alzheimer's cases, and two groups of resilient cases, which possessed pathology consistent with either high probability (HP, Braak stage V-VI and CERAD 2–3) or intermediate probability (IP, Braak state III-IV and CERAD 1–3) of Alzheimer's disease in the absence of dementia. We used a multivariate partial least squares regression approach to study differences in cytokine expression between resilient cases and both Alzheimer's and control cases. Our analysis identified distinct profiles of cytokines in the entorhinal cortex (one of the earliest and most severely affected brain regions in Alzheimer's disease) that are up-regulated in both HP and IP resilient cases relative to Alzheimer's and control cases. These cytokines, including IL-1β, IL-6, IL-13, and IL-4 in HP resilient cases and IL-6, IL-10, and IP-10 in IP resilient cases, delineate differential inflammatory activity in brains resilient to Alzheimer's pathology compared to Alzheimer's cases. Of note, these cytokines all have been associated with pathogen clearance and/or the resolution of inflammation. Moreover, our analysis in the superior temporal sulcus (a multimodal association cortex that consistently accumulates Alzheimer's pathology at later stages of the disease along with overt symptoms of dementia) revealed increased expression of neurotrophic factors, such as PDGF-bb and basic FGF in resilient compared to AD cases. The same region also had reduced expression of chemokines associated with microglial recruitment, including MCP-1 in HP resilient cases and MIP-1α in IP resilient cases compared to AD. Altogether, our data suggest that different patterns of cytokine expression exist in the brains of resilient and Alzheimer's cases, link these differences to reduced glial activation, increased neuronal survival and preserved cognition in resilient cases, and reveal specific cytokine targets that may prove relevant to the identification of novel mechanisms of brain resiliency to Alzheimer's pathology.

AB - Our group has previously studied the brains of some unique individuals who are able to tolerate robust amounts of Alzheimer's pathological lesions (amyloid plaques and neurofibrillary tangles) without experiencing dementia while alive. These rare resilient cases do not demonstrate the patterns of neuronal/synaptic loss that are normally found in the brains of typical demented Alzheimer's patients. Moreover, they exhibit decreased astrocyte and microglial activation markers GFAP and CD68, suggesting that a suppressed neuroinflammatory response may be implicated in human brain resilience to Alzheimer's pathology. In the present work, we used a multiplexed immunoassay to profile a panel of 27 cytokines in the brains of controls, typical demented Alzheimer's cases, and two groups of resilient cases, which possessed pathology consistent with either high probability (HP, Braak stage V-VI and CERAD 2–3) or intermediate probability (IP, Braak state III-IV and CERAD 1–3) of Alzheimer's disease in the absence of dementia. We used a multivariate partial least squares regression approach to study differences in cytokine expression between resilient cases and both Alzheimer's and control cases. Our analysis identified distinct profiles of cytokines in the entorhinal cortex (one of the earliest and most severely affected brain regions in Alzheimer's disease) that are up-regulated in both HP and IP resilient cases relative to Alzheimer's and control cases. These cytokines, including IL-1β, IL-6, IL-13, and IL-4 in HP resilient cases and IL-6, IL-10, and IP-10 in IP resilient cases, delineate differential inflammatory activity in brains resilient to Alzheimer's pathology compared to Alzheimer's cases. Of note, these cytokines all have been associated with pathogen clearance and/or the resolution of inflammation. Moreover, our analysis in the superior temporal sulcus (a multimodal association cortex that consistently accumulates Alzheimer's pathology at later stages of the disease along with overt symptoms of dementia) revealed increased expression of neurotrophic factors, such as PDGF-bb and basic FGF in resilient compared to AD cases. The same region also had reduced expression of chemokines associated with microglial recruitment, including MCP-1 in HP resilient cases and MIP-1α in IP resilient cases compared to AD. Altogether, our data suggest that different patterns of cytokine expression exist in the brains of resilient and Alzheimer's cases, link these differences to reduced glial activation, increased neuronal survival and preserved cognition in resilient cases, and reveal specific cytokine targets that may prove relevant to the identification of novel mechanisms of brain resiliency to Alzheimer's pathology.

KW - Alzheimer's disease

KW - Neuroinflammation

KW - Partial least squares regression

KW - Resilience

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U2 - 10.1016/j.nbd.2018.10.009

DO - 10.1016/j.nbd.2018.10.009

M3 - Article

C2 - 30336198

AN - SCOPUS:85056159660

SN - 0969-9961

VL - 121

SP - 327

EP - 337

JO - Neurobiology of Disease

JF - Neurobiology of Disease

ER -

Distinct cytokine profiles in human brains resilient to Alzheimer's pathology

Abstract

Keywords

UN SDGs

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