Neuroinflammation and Neurodegenerative Diseases: How Much Do We Still Not Know?

Abstract

The term "neuroinflammation" defines the typical inflammatory response of the brain closely related to the onset of many neurodegenerative diseases (NDs). Neuroinflammation is well known, but its mechanisms and pathways are not entirely comprehended. Some progresses have been achieved through many efforts and research. Consequently, new cellular and molecular mechanisms, diverse and conventional, are emerging. In listing some of those that will be the subject of our description and discussion, essential are the important roles of peripheral and infiltrated monocytes and clonotypic cells, alterations in the gut-brain axis, dysregulation of the apelinergic system, alterations in the endothelial glycocalyx of the endothelial component of neuronal vascular units, variations in expression of some genes and levels of the encoding molecules by the action of microRNAs (miRNAs), or other epigenetic factors and distinctive transcriptional factors, as well as the role of autophagy, ferroptosis, sex differences, and modifications in the circadian cycle. Such mechanisms can add significantly to understanding the complex etiological puzzle of neuroinflammation and ND. In addition, they could represent biomarkers and targets of ND, which is increasing in the elderly.

Keywords: emerging mechanisms; neurodegenerative diseases; neuroinflammation.

Figure 1

(by Biorender software version 04): Important drivers, i.e., alterations in the MGB axis, infections, and ischemia contribute to the activation and infiltration of circulating monocytes in the brain and their specific secretion of inflammation mediators. These latter influence the activation of other resident immune cells, thus leading to neuroinflammation and neurodegeneration. Similarly, clonotype cells influence neuroinflammation.

Figure 2

(A,B) (by Biorender software): Model describing the novel mechanisms involved in neuroinflammation and its relation to the onset of ND. In (A), it illustrates how the ferroptosis, autophagy, epigenetic factors, changes in circadian rhythm, and endothelial dysfunction associated with cerebrovascular insufficiency determine all the activation of NF-kB pathway through canonical or non-canonical signaling. In (B), it shows how activation of the NF-kB pathway through canonical or non-canonical signaling can activate a network of different signaling pathways, all related to the onset of neuroinflammation and the consequent onset of ND.

Figure 2

(A,B) (by Biorender software): Model describing the novel mechanisms involved in neuroinflammation and its relation to the onset of ND. In (A), it illustrates how the ferroptosis, autophagy, epigenetic factors, changes in circadian rhythm, and endothelial dysfunction associated with cerebrovascular insufficiency determine all the activation of NF-kB pathway through canonical or non-canonical signaling. In (B), it shows how activation of the NF-kB pathway through canonical or non-canonical signaling can activate a network of different signaling pathways, all related to the onset of neuroinflammation and the consequent onset of ND.