Fight Aging!

The research community has come to see chronic inflammation and other age-related immune system dysfunctions as an important aspect of neurodegenerative conditions. Inflammation in the short term is necessary for defense against pathogens and regeneration following injury. Unresolved, constant inflammation is harmful to tissue structure and function, however, changing cell behavior for the worse. In brain tissue, the effects of inflammatory signaling on the behavior of innate immune cells called microglia appears particularly important. Neurogenerative conditions are characterized by activated microglia. These microglia are less able to perform maintenance activities, while also contributing to loss of synapses and other pathological changes in the brain.

The authors of today's open access review paper take a broad view of the impact of immune system aging on the brain, and its potential roles in the development of neurodegenerative conditions. All such conditions exhibit changes in cellular biochemistry that can be linked to changed immune activity. Further, an inflammatory state appears correlated with onset and progression of these conditions. There is ample evidence for immunomodulatory, anti-inflammatory approaches to be a sensible way forward in the treatment of neurodegeneration, but adjusting the immune system is not straightforward. The fine details of the inflammatory mechanisms involved in pathology matter when it comes to building a better therapy.

Immunological aspects of central neurodegeneration

The etiology of various neurodegenerative disorders (NDs) 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.

While most central NDs appear to originate from genetic or environmental alterations of cellular homeostasis in the brain parenchyma, it is now clear that such perturbations are accompanied by the activation of innate and (at least in some cases) adaptive immune effector mechanisms that contribute to disease pathogenesis. Multiple NDs are associated with mutations in genes encoding components of the innate or adaptive immune system, such as TREM2 or HLA-DRB1. Moreover, hitherto unrecognized connections are emerging between central ND susceptibility genes, such as SNCA, and core immunological functions, such as the development of normal innate and adaptive immune reactions to bacterial challenges. Finally, patients affected by numerous NDs including Alzheimer's disease, Parkinson's disease, Huntington's disease, Lewy body dementia, and frontotemporal dementia exhibit shifts in the circulating levels of pro-inflammatory cytokines or peripheral immune populations, further supporting a pathogenic role for altered immune responses in the central nervous system in the progression of NDs.

With a few exceptions including the robust implication of CD4+ in disease pathogenesis in mouse models of Lewy body dementia, most of the current links between immunological mechanisms and ND pathogenesis rely on observational and correlative rather than mechanistic experimental setups. While at least partially this reflects the limited number of rodent models that recapitulate the emergence and progression of NDs in humans, it will be important to harness currently available models to implement antibody-mediated depletion, pharmacological inhibition, or genetic deletion/downregulation experiments to mechanistically link altered immune functions to ND pathogenesis and potentially identify novel targets for therapeutic interventions. While additional work is required to elucidate the actual therapeutic potential of immunotherapy for patients with central NDs, both innate and immune dysfunctions have been documented in the progression of NDs. It will be important to obtain further mechanistic insights into the immunological aspects of human degeneration in existing and newly developed rodent ND models to develop disease-modifying treatment options for these patient populations.