Neuroinflammation and neuroimmunology in Alzheimer's disease

Abstract

Neuroinflammation, mediated by activated glial cells and infiltrated lymphocytes, leads to the subsequent production of pro-inflammatory cytokines and related molecules. It is associated with the pathomechanisms of various neurodegenerative diseases, including Alzheimer's disease (AD). Microglia, innate immune cells in the central nervous system, are the principal component of neuroinflammation in health and disease. In particular, the phenotypic heterogeneity of microglia has been extensively examined through single-cell RNA sequencing technology, providing a clue to further understanding of neuroinflammation in AD and related neurological diseases. In addition, the role of brain lymphocytes has gained attention in the disease setting. In the past, the central nervous system is known to be an immuneprivileged tissue in which adaptive immunity and inflammation are highly restricted and controlled. However, an increasing number of reports show the detrimental and protective role of T lymphocytes in AD rodent models. In this issue of Clinical and Experimental Neuroimmunology, we invited three review articles by leading researchers in the fields of AD and neuroimmunology. Saito et al. reviewed the role of neuroinflammation in rodent models for AD. The authors have contributed significantly to the development of novel mouse models of AD, such as App knock-in mice. In this review, they focused on the role of the glial cell network in the AD continuum, the pathological sequence of amyloid β, tau and neurodegeneration in AD, and discussed the contribution of disease-associated microglia/homeostatic microglia in disease. Furthermore, they discussed the brain–periphery interaction in AD pathogenesis, which is a hot topic in AD research. Finally, multimorbidity in AD pathogenesis was discussed based on the clinical evidence. Chihara et al. reviewed the role of T lymphocytes in AD pathogenesis. Prominent T-lymphocyte infiltration, with its contribution to disease development and progression, is well known in multiple sclerosis. Increased permeability of the blood–brain barrier and infiltration of T lymphocytes have been documented in various studies using the human AD brain. In this regard, further investigation of the immune mechanisms resulting from T-cell infiltration into the central nervous system during disease initiation and exacerbation is required. They also provided an extensive review on the contribution of each subset of T lymphocytes in various AD models. Although the effects of each T lymphocyte on AD pathology are variable among AD mouse models, we need to carefully investigate the role of T lymphocytes in AD pathogenesis. Maekawa and Yamanaka reviewed the role of sex steroid hormone in AD, based on human and experimental evidence. As the incidence and prevalence of AD are dominant in women, the putative roles of sex hormones in AD pathology have been investigated. Although the role of estrogens was extensively investigated in the studies of AD mice and human subjects, the androgens also require attention, as they are capable of modifying neuroinflammation. In addition, humoral factors, such as hormones, certainly consist of the systemic or peripheral environment to affect the brain environment, ultimately altering the disease course. Finally, the three review articles by the experts will contribute to a further understanding of neuroinflammation and neuroimmunology in AD, leading to a better clue for future therapeutics for dementia.