Elsevier

Neurobiology of Disease

Volume 121, January 2019, Pages 327-337
Neurobiology of Disease

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

https://doi.org/10.1016/j.nbd.2018.10.009Get rights and content

Highlights

  • Certain individuals resist neurodegeneration despite robust Alzheimer's pathology.

  • Resilient cases are distinguished by unique cytokine expression profiles.

  • Cytokines associated with resiliency are neuroprotective and chemotactic.

  • Cytokine profiles may inform new strategies to combat Alzheimer's neurodegeneration.

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.

Introduction

Amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) are the classical pathological hallmarks of Alzheimer's disease (AD) (Montine et al. 2012a). Although it is widely assumed that plaques and tangles are causally related to the cognitive symptoms of dementia in AD, observations from several studies, including our earlier work, suggest that relationships between plaques, tangles and cognition are not especially strong and may not suffice to reliably predict clinical outcome on an individual basis (Ingelsson et al. 2004). We recently studied the brains of some unique individuals who seem to have an intrinsic capacity to withstand robust amounts of AD pathological lesions without experiencing dementia (Perez-Nievas et al. 2013). These rare resilient brains harbor plaque and tangle loads that in some cases are equivalent to those found in AD cases. However, they do not demonstrate the typical patterns of neuronal/synaptic loss seen in AD, and they exhibit a significantly decreased glial response, marked by GFAP and CD68 expression (Perez-Nievas et al. 2013), suggesting that down-regulated neuroinflammation is one of the differential traits of human brain resilience to AD pathology.

The role of neuroinflammation in AD continues to be uncertain. Some components of the inflammatory response, driven by astrocytes and microglia, may be beneficial to clear plaques and tangles. However, the increased expression of inflammatory mediators in the brains of patients with AD and several epidemiological studies linking the use of anti-inflammatory drugs with a decreased risk for dementia suggest that inflammation may be a driver of the disease (Wyss-Coray 2006). Evidence from in vitro and in vivo models suggest that neuroinflammation enhances production of oxidative species (Wilkinson and Landreth 2006), disrupts metabolic homeostasis, and promotes microglial-mediated synaptic loss (Hong et al. 2016). In addition, activated microglia express inflammatory cytokines such as IL-1α and TNF-α, both found to be up-regulated in AD brains (Tobinick et al. 2006; Wood et al. 2015; Ye et al. 2013), which in turn may contribute to astrocyte activation, further microglial activation, and cognitive dysfunction (Gibson et al. 2004; Rao et al. 2012).

Given the direct connection between glial activation and cytokine production, and the role of certain cytokines in neuronal and synaptic loss (Gibson et al. 2004; Hu et al. 2007), we hypothesized that resilient cases would exhibit a differential pattern of cytokine expression related to suppressed neuroinflammation, increased neuronal survival, and preserved cognition when compared to AD cases. In the present study, we have extended our prior characterization of phenotypic traits linked to resilience and AD pathology to include a multivariate analysis of a panel of neuropathological measures. We then quantified 27 immunomodulatory cytokines in four groups of subjects: 1) non-demented individuals whose post-mortem examination demonstrated absence of substantial AD pathology (control group), 2) non-demented individuals whose post-mortem examination demonstrated abundant AD pathology (high probability, HP resilient group with Braak stage V-VI and CERAD 2–3), 3) non-demented individuals whose post-mortem examination demonstrated moderate amounts of AD pathology (intermediate probability, IP resilient group with Braak stage III-IV and CERAD 1–3), and 4) individuals with AD pathology and pre-mortem dementia (AD group). Groups 2 and 3 represent a set of samples that exhibit ‘resiliency’ to neurodegeneration and dementia symptoms in response to the presence of classic AD pathology (plaques and tangles). These resilient groups, HP (group 2) and IP (group 3), also had cortical thickness similar to controls, intact neurite trajectory and axonal geometry, fewer neuritic dystrophies than AD cases, preserved expression of synaptic proteins, and low glial activation markers (GFAP and CD68). Our analysis focused on the entorhinal cortex (EC), a region particularly vulnerable to AD pathology at very early stages of disease, and the multimodal association cortex lining the superior temporal sulcus (STS) (Gómez-Isla et al. 1997), a region that consistently accumulates amyloid plaques and NFTs at later stages along with overt symptoms of dementia (Gomez-Isla et al. 1996). Due to the multidimensional nature of our data, we used a partial least squares regression analysis to identify differences in the cytokine expression profile between the four groups. Our data suggest that resilient cases exhibit distinct profiles of cytokine expression in the EC and STS that distinguish them from AD and control cases.

Section snippets

Brain Tissue Samples

Postmortem human brain tissue samples were collected from the Massachusetts General Hospital, Mayo Clinic, University of Pittsburgh, Columbia University and Washington University ADRC brain banks. Histological evaluation was performed on a specific set of blocked regions representative of a spectrum of neurodegenerative diseases. All blocks were stained with luxol fast blue and H&E, while selected blocks were routinely stained for Bielschowsky silver stain and Aβ, α-synuclein, ubiquitin and

Multivariate analysis of neuropathological variables differentiates resilient from AD cases

We have previously reported that some rare human brain samples seem to be resilient to robust burdens of amyloid and tau pathology (Perez-Nievas et al. 2013). Detailed neuropathological and biochemical assessments of the STS in these unique brains revealed a distinct phenotype characterized by increased neuronal survival and suppressed glial responses when compared to brains from demented AD patients. In the present work, we analyzed a collection of 12 neuropathological variables of interest

Discussion

Our prior finding of a suppressed glial reaction in resilient brains compared to AD, despite equivalent amounts of amyloid and tau deposits (Perez-Nievas et al. 2013), suggested that resilient cases may exhibit unique immune responses to Alzheimer's pathology. Since increased inflammatory cytokine expression is a key product and driver of glial response, we hypothesized that resilient cases would possess substantial differences in cytokine expression potentially linked to the lack of

Funding

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

Acknowledgments

We acknowledge the Massachusetts General Hospital, University of Pittsburgh, Mayo Clinic, Columbia University, and Washington University ADRCs, and WHICAP study participants and the research and support staff for their contributions to this study.

Declarations of interest

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.

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