Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2.

Elimination of apoptotic neurons without inflammation is crucial for brain tissue homeostasis, but the molecular mechanism has not been firmly established. Triggering receptor expressed on myeloid cells-2 (TREM2) is a recently identified innate immune receptor. Here, we show expression of TREM2 in microglia. TREM2 stimulation induced DAP12 phosphorylation, extracellular signal-regulated kinase phosphorylation, and cytoskeleton reorganization and increased phagocytosis. Knockdown of TREM2 in microglia inhibited phagocytosis of apoptotic neurons and increased gene transcription of tumor necrosis factor alpha and nitric oxide synthase-2, whereas overexpression of TREM2 increased phagocytosis and decreased microglial proinflammatory responses. Thus, TREM2 deficiency results in impaired clearance of apoptotic neurons and inflammation that might be responsible for the brain degeneration observed in patients with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy/Nasu-Hakola disease.

Innate immunity mediated by TLR9 modulates pathogenicity in an animal model of multiple sclerosis.

Inflammatory diseases of the CNS, such as MS and its animal model EAE, are characterized by infiltration of activated lymphocytes and phagocytes into the CNS. Within the CNS, activation of resident cells initiates an inflammatory cascade, leading to tissue destruction, demyelination, and neurologic deficit. TLRs recognize microbes and are pivotal mediators of innate immunity. Within the CNS, augmented TLR expression during EAE is observed, even in the absence of any apparent microbial involvement. To determine the functional relevance of this phenomenon during sterile autoimmunity, we studied the role of different TLRs as well as their common signaling adaptor MyD88 in the development of EAE. We found that MyD88 mice were completely EAE resistant. Surprisingly, this protection is partly due to engagement of the CpG receptor TLR9. Restricting the MyD88 or TLR9 mutation to host radio-resistant cells, including the cells within the CNS, revealed that engagement of radio-resistant cells modulated the disease course and histopathological changes. Our data clearly demonstrate that both TLR9 and MyD88 are essential modulators of the autoimmune process during the effector phase of disease and suggest that endogenous "danger signals" modulate the disease pathogenesis.

A cytoarchitectonic study of the hippocampal formation of the tree shrew (Tupaia belangeri).

Tree shrews constitute an interesting animal model to study the impact of stress or aging on the hippocampal formation, a brain structure known to be affected under such environmental or internal influences. To perform detailed investigations of the hippocampal formation, adequate knowledge of its anatomy should be present. Until now, the hippocampal formation of the tree shrew has not yet been studied extensively. The main objective of this study, therefore, was to describe the subfield boundaries in various levels of the dorsoventral hippocampal axis of the tree shrew (Tupaia belangeri) in detail. The secondary aim was to clarify whether a separate CA2 field can actually be distinguished in the tree shrew hippocampus, a fact that was denied in former reports. In addition, we aimed at investigating whether or not a CA4 subfield can be identified in the tree shrew's hippocampus. The immunocytochemical distribution of microtubule-associated protein 2 and the calcium-binding proteins, parvalbumin and calbindin, and the characteristics of Nissl staining in adjacent sections were compared. Because of the rather dorsoventral orientation of the long hippocampal axis in tree shrews, staining patterns were analyzed mainly in horizontal sections. The subiculum and the hippocampal CA1 and CA3 areas were easily identified. Moreover, we were able to demonstrate the existence of a distinct CA2 subfield in the tree shrew's Ammon's horn, contrary to previous reports. However, our results indicate that a CA4 field in the tree shrew hippocampal formation cannot be identified with the methods that we used. Therefore, supposed CA4 pyramidal neurons should be included into the CA3 field.