Fig. 1

Central and peripheral inflammatory/immune response in neurodegeneration. Upon injury, disease, or inflammation, damaged neurons could release self-antigens or modified proteins that activate resting microglia. Activated microglia responds to these stimuli, by production of proinflammatory cytokines and chemokines, reactive oxygen, and nitrogen species. When such first innate immune-related process is not completely resolutive and the inflammatory stimuli persist, the microglia-mediated mechanisms remain trapped in a vicious cycle, characterized by chronic pro-inflammatory cytokine production linked to a cascade of neurotoxic events leading to neuronal death. Substantial recruitment of monocytes into the AD brain begins when Aβ deposition and associated neuronal damage triggers a local immune response, activating astrocytes and microglia. Activated pro-inflammatory microglia also release astrocyte-activating signals which induce neuroinflammatory astrocytes that, in turn, amplify the neurodegenerative cycle. In addition, misfolded proteins not adequately removed may drain into peripheral lymphoid tissues, wherein they are presented by antigen presenting cells to naïve T cells, thereafter mounting an adaptive immune response against these antigens. Depending upon antigen-presenting cell signals, naïve T cells differentiate into antigen-specific T effector cells (Th1, Th2, Th17, and cytotoxic T lymphocytes (CTL) or regulatory T (Treg) cells). Specifically, Th1 and Th17 cells cross the blood-brain barrier and directly contribute to neuroinflammation through the production of neurotoxic and proinflammatory factors that act on glial cells. Consequently, activated microglia and astrocytes respond by releasing high amounts of chemokines that assist the infiltration of a second wave of effector T cells into the brain. CD8+ CTLs recognize antigen presented by MHC class I on neurons to induce perforin- and/or granzyme-mediated cytolysis. In response to inflammatory events, Treg cells dampen down neuroinflammation and neurodegeneration