Inflammation as common link to progressive neurological diseases

Abstract

Life expectancy has increased immensely over the past decades, bringing new challenges to the health systems as advanced age increases the predisposition for many diseases. One of those is the burden of neurologic disorders. While many hypotheses have been placed to explain aging mechanisms, it has been widely accepted that the increasing pro-inflammatory status with advanced age or "inflammaging" is a main determinant of biological aging. Furthermore, inflammaging is at the cornerstone of many age-related diseases and its involvement in neurologic disorders is an exciting hypothesis. Indeed, aging and neurologic disorders development in the elderly seem to share some basic pathways that fundamentally converge on inflammation. Peripheral inflammation significantly influences brain function and contributes to the development of neurological disorders, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Understanding the role of inflammation in the pathogenesis of progressive neurological diseases is of crucial importance for developing effective treatments and interventions that can slow down or prevent disease progression, therefore, decreasing its social and economic burden.

Keywords: Central nervous system; Cytokines; Immune response; Neurodegeneration; Neuroinflammation.

Fig. 1

Neuropathological changes occurring in Alzheimer’s disease brain, emphasizing key features of the disease. Created with BioRender.com

Fig. 2

Schematic illustration of the sequence of events in Alzheimer’s disease (AD) and peripheral inflammation, emphasizing the interplay between these two processes. Circulating cytokines can cross the blood–brain barrier (BBB) and stimulate neuroglial cells (mainly astrocytes and microglia) to produce in situ more inflammatory mediators. Those inflammatory mediators can, in turn, stimulate other neuroglial cells, but also activate other signaling cascades such as the Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). The JNK/p38-MAPK induces the activity of γ-secretase increasing the production of Aβ peptides and amyloid plaques. These plaques cause neurodegeneration and its accumulation, in the pro-inflammatory environment, leads to hyperphosphorylation of Tau and formation of the neurofibrillary tangles (NFTs). Created with BioRender.com

Fig. 3

Illustrative representation of the effects of Parkinson’s disease (PD) in the brain and listing of motor and non-motor skill symptoms. Degeneration of pigmented dopaminergic neurons in the midbrain and misfolded α-synuclein and consequential accumulation of Lewis bodies are the hallmarks of PD. The neuronal loss causes dysfunction of the nigrostriatal pathway with a decrease in the levels of dopamine. Usually, this later pathway impairment results in the cardinal motor symptoms of PD. Created with BioRender.com

Fig. 4

Schematic representation of the sequence of events in multiple sclerosis (MS). Active leukocytes and circulating pro-inflammatory cytokines (green dotes) disrupt the blood–brain barrier (BBB) and infiltrate the central nervous system (CNS) parenchyma. The primed T cells interact with B cells to produce antibodies against the components of the myelin sheet. Furthermore, T cells also interact with microglia to release antibodies and cytokines that further destroy the myelin sheet. Created with BioRender.com

Fig. 5

Schematic representation of the immune cells that mediate multiple sclerosis (MS). T cell receptors (TCR) can recognize antigens but do not bind directly, they require antigen-presenting cells (APC). APC express histocompatibility complex (MHC), of which, MHC class I presents antigens to cytotoxic T cells and MHC class II present to helper T cells. Furthermore, to make the connection between the TCR and MHC, the T cells express co-receptors. Usually, the cytotoxic T cells express the CD8 co-receptor, and the helper T cells express the CD4 co-receptor. The cytotoxic T cells can directly kill infected cells. The helper T cell can be divided into different phenotypes according to the specific pattern of cytokines secreted. Created with Biorender.com