Brain interleukins and Alzheimer's disease

Abstract

The central nervous system (CNS) is immune-privileged by several immuno-modulators as interleukins (ILs). ILs are cytokines secreted by immune cells for cell-cell signaling communications and affect the functions of the CNS. ILs were reported to orchestrate different molecular and cellular mechanisms of both physiological and pathological events, through overproduction or over-expression of their receptors. They interact with numerous receptors mediating pro-inflammatory and/or anti-inflammatory actions. Interleukins have been implicated to participate in neurodegenerative diseases. They play a critical role in Alzheimer's disease (AD) pathology which is characterized by the over-production of pro-inflammatory ILs. These may aggravate neurodegeneration, in addition to their contribution to detrimental mechanisms as oxidative stress, and excitotoxicity. However, recent research on the relation between ILs and AD revealed major discrepancies. Most of the major ILs were shown to play both pro- and anti-inflammatory roles in different experimental settings and models. The interactions between different ILs through shared pathways also add to the difficulty of drawing solid conclusions. In addition, targeting the different ILs has not yielded consistent results. The repeated failures of therapeutic drugs in treating AD necessitate the search for novel agents targeting multiple mechanisms of the disease pathology. In this context, the understanding of interleukins and their roles throughout the disease progression and interaction with other systems in the brain may provide promising therapeutic targets for the prevention or treatment of AD.

Keywords: Alzheimer’s disease; Excitotoxicity; Inflammation; Interleukins; Oxidative stress.

Fig. 1

Microglial phenotypes and functions in AD stages

Fig. 2

The actions of the pro-inflammatory ILs, IL-1 and IL-6, and the anti-inflammatory ILs, IL-10, IL-4 and IL-13

Fig. 3

The role of anti-inflammatory ILs in AD

Fig. 4

The different mechanisms caused by brain injury to result in neurodegeneration. Any insult in the brain results in inflammation, where IL-17 release causes other ILs to be released like IL-1, IL-6, IL-8 and IL-18 that act on their receptors to activate different neuronal and immune cells to stimulate two different cascades: immunological and non-immunological. The immunological cascade causes inflammation progression which results in 1. Myelin & axon damage, 2.BBB damage, 3. Hyperexcitability and 4. Oxidative stress. The non-immunological cascade affects glutamate release causing peroxynitrite formation that results in 1. Lipid peroxidation, 2. Protein denaturation and 3. DNA damage. Finally, all these events result in neurodegeneration