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

Research output: Contribution to journalArticlepeer-review

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 & 1 more Teresa Gomez-Isla

Original languageEnglish
Pages (from-to)327-337
Number of pages11
JournalNeurobiology of Disease
PublishedJan 2019

Bibliographical 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: © 2018 Elsevier Inc. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.

King's Authors


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.

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