Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment but strongly interacts with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on micro- and astroglia and trigger an innate immune response, characterized by the release of inflammatory mediators, which contribute to disease progression and severity. Genome wide analysis suggests that several genes, which increase the risk for sporadic Alzheimer's disease en-code for factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity are likely to interfere with the immunological processes of the brain and further promote disease progression. This re-view provides an overview on the current knowledge and focuses on the most recent and exciting findings. Modulation of risk factors and intervention with the described immune mechanisms are likely to lead to future preventive or therapeutic strategies for Alzheimer's disease.

Summary Microglia play critical roles in brain development, homeostasis, and neurological disorders. Here, we report that human microglial-like cells (iMGL) can be differentiated from iPSCs to study their function in neurological diseases, like Alzheimer’s disease (AD). We find that iMGLs develop in vitro similarly to microglia in vivo and whole transcriptome analysis demonstrates that they are highly similar to cultured adult and fetal human microglia. Functional assessment of iMGLs reveals that they secrete cytokines in response to inflammatory stimuli, migrate and undergo calcium transients, and robustly phagocytose CNS substrates. iMGLs were used to examine the effects of Aβ fibrils and brain-derived tau oligomers on AD-related gene expression and to interrogate mechanisms involved in synaptic pruning. Furthermore, iMGLs transplanted into transgenic mice and human brain organoids resemble microglia in vivo. Together, these findings demonstrate that iMGLs can be used to study microglial function, providing important new insight into human neurological disease.

SummaryCentral nervous system (CNS) immune privilege is an experimentally defined phenomenon. Tissues that are rapidly rejected by the immune system when grafted in sites, such as the skin, show prolonged survival when grafted into the CNS. Initially, CNS immune privilege was construed as CNS isolation from the immune system by the blood-brain barrier (BBB), the lack of draining lymphatics, and the apparent immunoincompetence of microglia, the resident CNS macrophage. CNS autoimmunity and neurodegeneration were presumed automatic consequences of immune cell encounter with CNS antigens. Recent data have dramatically altered this viewpoint by revealing that the CNS is neither isolated nor passive in its interactions with the immune system. Peripheral immune cells can cross the intact BBB, CNS neurons and glia actively regulate macrophage and lymphocyte responses, and microglia are immunocompetent but differ from other macrophage/dendritic cells in their ability to direct neuroprotective lymphocyte responses. This newer view of CNS immune privilege is opening the door for therapies designed to harness autoreactive lymphocyte responses and also implies (i) that CNS autoimmune diseases (i.e. multiple sclerosis) may result as much from neuronal and/or glial dysfunction as from immune system dysfunctions and (ii) that the severe neuronal and glial dysfunction associated with neurodegenerative disorders (i.e. Alzheimer's disease) likely alters CNSspecific regulation of lymphocyte responses affecting the utility of immune-based therapies (i.e. vaccines).

No abstract

Microglial activation is an early and common feature of almost all neuropathologies, including multiple sclerosis, Alzheimer's disease and mechanical injury. To better understand the relative contributions microglia make toward neurodegeneration and neuroprotection, we used TOGA Ò to identify molecules expressed by microglia and regulated by inflammatory signals. Triggering receptor expressed on myeloid cells-2 (TREM-2) was among the mRNAs identified as being expressed by unactivated microglia, but down-regulated by lipopolysaccharide/interferon c. In the healthy CNS, not all microglia expressed TREM-2. Microglial expression of TREM-2 varied not only between brain regions but also within each brain region. Brain regions with an incomplete blood-brain barrier had the lowest percentages of TREM-2-expressing microglia, whereas the lateral entorhinal and cingulate cortex had the highest percentages. A novel form of TREM-2b that lacked a transmembrane domain was detected, perhaps indicating a soluble form of the protein. Taken together, these data suggest that (1) subsets of microglia are specialized to respond to defined extracellular signals; and (2) Tissue-specific inflammation is dependent on more than simply the presence of an antigen within a tissue and an immune response mounted against that antigen. The onset, progression and termination of inflammatory responses are largely dependent on how the resident tissue macrophage/ dendritic cell interacts with both stromal tissue and tissueinfiltrating immune cells (Medzhitov and Janeway 1998;Lo et al. 1999). These interactions can shape antigen-independent and antigen-dependent immune responses toward the production of toxic molecules capable of destroying not only pathogens but also the tissues themselves. Such events have been argued to contribute to catastrophic neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease and stroke (Kreutzberg 1996;Stoll and Jander 1999;Becher et al. 2000;Streit 2000;Aloisi 2001;Schwab et al. 2001;Campanella et al. 2002;Togo et al. 2002). Antigen presentation within the CNS by either microglia and/or CNS-infiltrating macrophages/dendritic cells may also mute and may potentially redirect antigen-specific immune responses toward the production of trophic factors (Ford et al. 1996;Raivich et al. 1998;Carson et al. 1999a;Kerschensteiner et al. 1999;Serpe et al. 1999). Such interactions have been suggested to contribute to the generation of immunological privilege and promotion of neuronal survival in the CNS (Schwartz et al. 1999;Streit 2000).The tissue macrophages of the brain are the microglia (Kreutzberg 1996;Streit 2000;Aloisi 2001). They are found in all brain regions, often in close apposition with neurons, and comprise between 5 and 15% of cells in the CNS. Abbreviations used: BBB, blood-brain barrier; Ct, cycle threshold; IRG, interferon response gene; IFN, interferon; LPS, lipolysaccharide; MHC, major histocompatibility complex; SSC, saline sodium citrate buffer; svTREM-2b, splice variant of triggerin...