Immunological aspects of central neurodegeneration

Abstract

The etiology of various neurodegenerative disorders that mainly affect the central nervous system including (but not limited to) Alzheimer's disease, Parkinson's disease and Huntington's disease has classically been attributed to neuronal defects that culminate with the loss of specific neuronal populations. However, accumulating evidence suggests that numerous immune effector cells and the products thereof (including cytokines and other soluble mediators) have a major impact on the pathogenesis and/or severity of these and other neurodegenerative syndromes. These observations not only add to our understanding of neurodegenerative conditions but also imply that (at least in some cases) therapeutic strategies targeting immune cells or their products may mediate clinically relevant neuroprotective effects. Here, we critically discuss immunological mechanisms of central neurodegeneration and propose potential strategies to correct neurodegeneration-associated immunological dysfunction with therapeutic purposes.

Fig. 1. Immunological aspects of Alzheimer’s disease.

Alzheimer’s disease (AD) develops in the context of complex immunological alterations that involve not only microglial cells, with a major role for altered apolipoprotein E (APOE) and triggering receptor expressed on myeloid cells 2 (TREM2) signalling, but also astrocytes and oligodendrocytes, culminating with a neuroinflammatory state associated with immune cell infiltration from the periphery. Aβ amyloid beta, BBB blood-brain barrier, C1QA complement C1q A chain, DA disease-associated, IFN interferon, IL1A interleukin 1A, SERPINA3 serpin family A member 3, tau (microtubule-associated protein tau, MAPT), TGFB1 transforming growth factor beta 1, TNF tumor necrosis factor. Created with BioRender.com.

Fig. 2. Immunological aspects of Parkinson’s disease.

Patients with Parkinson’s disease (PD) exhibit synuclein alpha (SNCA)-related microglial activation coupled with the initiation of multiple signalling pathways that result in the abundant secretion of pro-inflammatory cytokines in the cerebrospinal fluid (CSF). Such cytokines promote the recruitment of immune cells that contribute to neuroinflammation by secreting proinflammatory mediators such as interferon gamma (IFNG). BBB blood brain barrier, IL interleukin, TNF tumor necrosis factor, T_REG regulatory T. Created with BioRender.com.

Fig. 3. Immunological aspects of Huntington’s disease.

Huntingtin (HTT) defects as caused by the mutations that drive Huntington’s disease (HD) foster a robust neuroinflammatory process involving microglial cells as well as astrocytes and oligodendrocytes that is often associated with a T_H17-polarized CD4⁺ T cell response dominated by the secretion of pro-inflammatory cytokines like interleukin 8 (IL8), IL17A and tumor necrosis factor (TNF). BBB blood brain barrier, mHTT mutant huntingtin. Created with BioRender.com.