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Cited by 133Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

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

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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. +13 more·2019·Neurobiology of Disease
DOI 10.1016/j.nbd.2018.10.009PMC PMC6437670
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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.

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Authors
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., Wood, L. B., & Gomez-Isla, T.
Affiliations
  • Georgia Institute of Technology (US)
  • Harvard University (US)
  • Mayo Clinic (US)
  • Washington University in St. Louis (US)
  • University of Pittsburgh (US)
  • Columbia University Irving Medical Center (US)
Corresponding author
Wood, Levi B.
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2019-01
Volume
121
Pages
327-337
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2018.10.009
PMC
PMC6437670
OpenAlex
W2897731590
Cited by
133
References
14
Citations by year
2026: 13 · 2025: 17 · 2024: 19 · 2023: 15 · 2022: 15 · 2021: 28 · 2020: 20 · 2019: 6
FWCI
9.28
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Disease (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (UF1 AG032438, P50 AG005133, R01AG043511, P50 AG005134, U01AG016976, T32-GM008433)
  • National Center for Advancing Translational Sciences (UL1TR001873)
  • National Cancer Institute
  • Georgia Institute of Technology
  • Cure Alzheimer's Fund
  • Mayo Clinic
  • Bayer Schering
  • National Institute on Aging
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, brain resilience, cytokine profile, neuroinflammation, entorhinal cortex, superior temporal sulcus, amyloid plaques, neurofibrillary tangles, microglial activation, astrocyte activation, neurotrophic factors, chemokines, MCP-1, MIP-1α, PDGF-BB, basic FGF, interleukin-6
MeSH terms
Aged, 80 and over, Alzheimer Disease, Brain, Encephalitis, Female, Humans, Male, Severity of Illness Index, Up-Regulation, Multivariate Analysis, Least-Squares Analysis, Cytokines, Neurofibrillary Tangles, Inflammation Mediators, Plaque, Amyloid

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