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Distinct cytokine profiles in human brains resilient to Alzheimer's pathology.
Neurobiol Dis 2019; 121:327-337ND

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.

Authors+Show Affiliations

Massachusetts General Hospital ADRC, Harvard University, 15 Parkman St #835, Boston, MA 02114, United States.Parker H. Petit Institute for Bioengineering & Bioscience, Georgia Institute of Technology, 315 Ferst Dr, Atlanta, GA 30332, United States; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, North Ave NW, Atlanta, GA 30332, United States. Electronic address: lweinstock3@gatech.edu.Massachusetts General Hospital ADRC, Harvard University, 15 Parkman St #835, Boston, MA 02114, United States.Massachusetts General Hospital ADRC, Harvard University, 15 Parkman St #835, Boston, MA 02114, United States.Massachusetts General Hospital ADRC, Harvard University, 15 Parkman St #835, Boston, MA 02114, United States.Massachusetts General Hospital ADRC, Harvard University, 15 Parkman St #835, Boston, MA 02114, United States. Electronic address: AAMARAL@mgh.harvard.edu.Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL 32224, United States. Electronic address: Murray.Melissa@mayo.edu.Department of Neurology, Knight Alzheimer Disease Research Center, Washington University, 1 Brookings Dr, St. Louis, MO 63130, United States. Electronic address: moulderk@abraxas.wustl.edu.Department of Neurology, Knight Alzheimer Disease Research Center, Washington University, 1 Brookings Dr, St. Louis, MO 63130, United States. Electronic address: jcmorris@wustl.edu.Department of Neurology, Knight Alzheimer Disease Research Center, Washington University, 1 Brookings Dr, St. Louis, MO 63130, United States. Electronic address: cairnsn@neuro.wustl.edu.Department of Neurology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, United States. Electronic address: Parisi.joseph@mayo.edu.Department of Radiology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, United States. Electronic address: vlowe@mayo.edu.Department of Neurology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, United States. Electronic address: peter8@mayo.edu.Department of Pathology, University of Pittsburgh School of Medicine, 4200 Fifth Ave, Pittsburgh, PA 15260, United States. Electronic address: koflerjk@upmc.edu.Department of Neurology, University of Pittsburgh School of Medicine, 4200 Fifth Ave, Pittsburgh, PA 15260, United States; Department of Psychiatry, University of Pittsburgh School of Medicine, 3811 DeSoto Street, Pittsburgh, PA 15260, United States. Electronic address: ikonomovicmd@upmc.edu.Department of Neurology, University of Pittsburgh School of Medicine, 4200 Fifth Ave, Pittsburgh, PA 15260, United States. Electronic address: lopezol@upmc.edu.Department of Psychiatry, University of Pittsburgh School of Medicine, 3811 DeSoto Street, Pittsburgh, PA 15260, United States.The Taub Institute for Research on Alzheimer's Disease and the Aging Brain and The Gertrude H. Sergievsky Center, Columbia University, 116th St & Broadway, New York, NY 10027, United States. Electronic address: rpm2@cumc.columbia.edu.Massachusetts General Hospital ADRC, Harvard University, 15 Parkman St #835, Boston, MA 02114, United States. Electronic address: MFROSCH@mgh.harvard.edu.Parker H. Petit Institute for Bioengineering & Bioscience, Georgia Institute of Technology, 315 Ferst Dr, Atlanta, GA 30332, United States; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, North Ave NW, Atlanta, GA 30332, United States; Georgia W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, 315 Ferst Dr, Atlanta, GA 30332, United States; Beth Israel Deaconess Cancer Center, 330 Brookline Ave, Boston, MA 02215, United States. Electronic address: levi.wood@me.gatech.edu.Massachusetts General Hospital ADRC, Harvard University, 15 Parkman St #835, Boston, MA 02114, United States. Electronic address: TGOMEZISLA@mgh.harvard.edu.

Pub Type(s)

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

Language

eng

PubMed ID

30336198

Citation

Barroeta-Espar, Isabel, et al. "Distinct Cytokine Profiles in Human Brains Resilient to Alzheimer's Pathology." Neurobiology of Disease, vol. 121, 2019, pp. 327-337.
Barroeta-Espar I, Weinstock LD, Perez-Nievas BG, et al. Distinct cytokine profiles in human brains resilient to Alzheimer's pathology. Neurobiol Dis. 2019;121:327-337.
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, pp. 327-337. doi:10.1016/j.nbd.2018.10.009.
Barroeta-Espar I, et al. Distinct Cytokine Profiles in Human Brains Resilient to Alzheimer's Pathology. Neurobiol Dis. 2019;121:327-337. PubMed PMID: 30336198.
* Article titles in AMA citation format should be in sentence-case
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, Y1 - 2018/10/15/ PY - 2018/07/11/received PY - 2018/10/03/revised PY - 2018/10/12/accepted PY - 2018/10/20/pubmed PY - 2019/11/22/medline PY - 2018/10/19/entrez KW - Alzheimer's disease KW - Neuroinflammation KW - Partial least squares regression KW - Resilience SP - 327 EP - 337 JF - Neurobiology of disease JO - Neurobiol. Dis. VL - 121 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. SN - 1095-953X UR - https://www.unboundmedicine.com/medline/citation/30336198/Distinct_cytokine_profiles_in_human_brains_resilient_to_Alzheimer's_pathology_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-9961(18)30713-7 DB - PRIME DP - Unbound Medicine ER -