ABSTRACT
Chronic inflammation contributes to neuronal death in Alzheimer's disease (AD) and frontotemporal dementia (FTD). Here we evaluated inflammatory and pro-resolving mediators in AD and behavioural variant of FTD (bvFTD) patients compared with controls, since neuroinflamamtion is a common feature in both diseases. Ninety-eight subjects were included in this study, divided into AD (nâ¯=â¯32), bvFTD (nâ¯=â¯30), and control (nâ¯=â¯36) groups. The levels of hsCRP, IL-1ß, IL-6, TNF, and TGF-ß1, as well as annexin A1 (AnxA1) and lipoxin A4 (LXA4) were measured in blood and cerebrospinal fluid (CSF). The expression profile of AnxA1 was evaluated in peripheral blood mononuclear cells (PBMCs) as well the distribution of ANXA1 rs2611228 polymorphism. We found reduced peripheral levels of hsCRP and TNF in AD compared with bvFTD patients and controls, and increased levels of TGF-ß1 in AD compared to controls. Moreover, reduced plasma levels of AnxA1 were observed in bvFTD compared to AD and controls. There was a significant cleavage of AnxA1 in PBMCs in both dementia groups. The results suggest differential regulation of inflammatory and pro-resolving mediators in bvFTD and AD, while AnxA1 cleavage may impair pro-resolving mechanisms in both groups.
Subject(s)
Alzheimer Disease/metabolism , Annexin A1/metabolism , Cytokines/metabolism , Frontotemporal Dementia/metabolism , Lipoxins/metabolism , Aged , Aged, 80 and over , Alzheimer Disease/immunology , Annexin A1/blood , Annexin A1/cerebrospinal fluid , Cytokines/blood , Cytokines/cerebrospinal fluid , Diagnosis, Differential , Female , Frontotemporal Dementia/immunology , Genotype , Healthy Volunteers , Humans , Inflammation , Lipoxins/blood , Lipoxins/cerebrospinal fluid , Male , Middle AgedABSTRACT
BACKGROUND: Resolution is the final stage of the inflammatory response, when restoration of tissue occurs. Failure may lead to chronic inflammation, which is known as part of the pathology in the brain of individuals with Alzheimer's disease (AD). METHODS: Specialized pro-resolving mediators (SPMs), receptors, biosynthetic enzyme, and downstream effectors involved in resolution were analyzed in postmortem hippocampal tissue from AD patients and non-AD subjects. SPMs were analyzed in cerebrospinal fluid (CSF). RESULTS: SPMs and SPM receptors were detected in the human brain. Levels of the SPM lipoxin A4 (LXA4) were reduced in AD, both in the CSF and hippocampus. An enzyme involved in LXA4 synthesis and two SPM receptors were elevated in AD brains. LXA4 and RvD1 levels in CSF correlated with Mini-Mental State Examination (MMSE) scores. CONCLUSIONS: A resolution pathway exists in the brain and the alterations described herein strongly suggest a dysfunction of this pathway in AD. MMSE correlations suggest a connection with cognitive function in AD.
