WashU weekly Neuroscience publications

Distinct cytokine profiles in human brains resilient to Alzheimer’s pathology
(2019) Neurobiology of Disease, 121, pp. 327-337. 

Barroeta-Espar, I.^a , Weinstock, L.D.^{b c} , Perez-Nievas, B.G.^a , Meltzer, A.C.^a , Siao Tick Chong, M.^a , Amaral, A.C.^a , Murray, M.E.^e , Moulder, K.L.^f , Morris, J.C.^f , Cairns, N.J.^f , Parisi, J.E.^d , Lowe, V.J.^g , Petersen, R.C.^d , Kofler, J.^h , Ikonomovic, M.D.^{i j} , López, O.ⁱ , Klunk, W.E.^j , Mayeux, R.P.^k , Frosch, M.P.^a , Wood, L.B.^{b c l m} , Gomez-Isla, T.^a

^a Massachusetts General Hospital ADRC, Harvard University, 15 Parkman St #835, Boston, MA 02114, United States
^b Parker H. Petit Institute for Bioengineering & Bioscience, Georgia Institute of Technology, 315 Ferst Dr, Atlanta, GA 30332, United States
^c Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, North Ave NW, Atlanta, GA 30332, United States
^d Department of Neurology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, United States
^e Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL 32224, United States
^f Department of Neurology, Knight Alzheimer Disease Research Center, Washington University, 1 Brookings Dr, St. Louis, MO 63130, United States
^g Department of Radiology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, United States
^h Department of Pathology, University of Pittsburgh School of Medicine, 4200 Fifth Ave, Pittsburgh, PA 15260, United States
ⁱ Department of Neurology, University of Pittsburgh School of Medicine, 4200 Fifth Ave, Pittsburgh, PA 15260, United States
^j Department of Psychiatry, University of Pittsburgh School of Medicine, 3811 DeSoto Street, Pittsburgh, PA 15260, United States
^k 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
^l Georgia W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, 315 Ferst Dr, AtlantaGA 30332, United States
^m Beth Israel Deaconess Cancer Center, 330 Brookline Ave, Boston, MA 02215, United States

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. © 2018 Elsevier Inc.

Author Keywords
Alzheimer’s disease;  Neuroinflammation;  Partial least squares regression;  Resilience

Document Type: Article
Source: Scopus