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 Lowe, Ronald Carl Petersen, Julia Kofler, Milos D. Ikonomovic, Oscar López, William E. Klunk, Richard P. Mayeux, Matthew P. Frosch, Levi B. Wood & 1 others Teresa Gomez-Isla

Research output: Contribution to journalArticle

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.

LanguageEnglish (US)
Pages327-337
Number of pages11
JournalNeurobiology of Disease
Volume121
DOIs
StatePublished - Jan 1 2019

Fingerprint

Pathology
Cytokines
Brain
Dementia
Interleukin-6
Chemokine CCL3
Entorhinal Cortex
Neurofibrillary Tangles
Interleukin-13
Amyloid Plaques
Nerve Growth Factors
Temporal Lobe
Least-Squares Analysis
Chemokines
Immunoassay
Neuroglia
Astrocytes
Interleukin-4
Interleukin-10
Cognition

Keywords

  • Alzheimer's disease
  • Neuroinflammation
  • Partial least squares regression
  • Resilience

ASJC Scopus subject areas

  • Neurology

Cite this

Barroeta-Espar, I., Weinstock, L. D., Perez-Nievas, B. G., Meltzer, A. C., Siao Tick Chong, M., Amaral, A. C., ... 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

Distinct cytokine profiles in human brains resilient to Alzheimer's pathology. / Barroeta-Espar, Isabel; Weinstock, Laura D.; Perez-Nievas, Beatriz G.; Meltzer, Avery C.; Siao Tick Chong, Michael; Amaral, Ana C.; Murray, Melissa E; Moulder, Krista L.; Morris, John C.; Cairns, Nigel J.; Parisi, Joseph E; Lowe, Val; Petersen, Ronald Carl; Kofler, Julia; Ikonomovic, Milos D.; López, Oscar; Klunk, William E.; Mayeux, Richard P.; Frosch, Matthew P.; Wood, Levi B.; Gomez-Isla, Teresa.

In: Neurobiology of Disease, Vol. 121, 01.01.2019, p. 327-337.

Research output: Contribution to journalArticle

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, V, 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
Barroeta-Espar I, Weinstock LD, Perez-Nievas BG, Meltzer AC, Siao Tick Chong M, Amaral AC et al. Distinct cytokine profiles in human brains resilient to Alzheimer's pathology. Neurobiology of Disease. 2019 Jan 1;121:327-337. https://doi.org/10.1016/j.nbd.2018.10.009
Barroeta-Espar, Isabel ; Weinstock, Laura D. ; Perez-Nievas, Beatriz G. ; Meltzer, Avery C. ; Siao Tick Chong, Michael ; Amaral, Ana C. ; Murray, Melissa E ; Moulder, Krista L. ; Morris, John C. ; Cairns, Nigel J. ; Parisi, Joseph E ; Lowe, Val ; Petersen, Ronald Carl ; Kofler, Julia ; Ikonomovic, Milos D. ; López, Oscar ; Klunk, William E. ; Mayeux, Richard P. ; Frosch, Matthew P. ; Wood, Levi B. ; Gomez-Isla, Teresa. / Distinct cytokine profiles in human brains resilient to Alzheimer's pathology. In: Neurobiology of Disease. 2019 ; Vol. 121. pp. 327-337.
@article{74e2a51f6e314de1975179ee991b4b93,
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 Val Lowe and Petersen, {Ronald Carl} 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",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.nbd.2018.10.009",
language = "English (US)",
volume = "121",
pages = "327--337",
journal = "Neurobiology of Disease",
issn = "0969-9961",
publisher = "Academic Press Inc.",

}

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

AU - Petersen, Ronald Carl

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

PY - 2019/1/1

Y1 - 2019/1/1

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

UR - http://www.scopus.com/inward/record.url?scp=85056159660&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056159660&partnerID=8YFLogxK

U2 - 10.1016/j.nbd.2018.10.009

DO - 10.1016/j.nbd.2018.10.009

M3 - Article

VL - 121

SP - 327

EP - 337

JO - Neurobiology of Disease

T2 - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

ER -