SUMMARY Microglia play a pivotal role in maintenance of brain homeostasis, but lose homeostatic function during neurodegenerative disorders. We identified a specific apolipoprotein E (APOE)-dependent molecular signature in microglia from models of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Alzheimer’s disease (AD) and in microglia surrounding neuritic β-amyloid (Aβ) -plaques in human AD brains. The APOE pathway mediated a switch from a homeostatic to neurodegenerative microglia phenotype following phagocytosis of apoptotic neurons. Triggering receptor expressed on myeloid cells 2 (TREM2) induced APOE signaling, and targeting the TREM2-APOE pathway restored the homeostatic signature of microglia in ALS and AD mouse models and prevented neuronal loss in an acute model of neurodegeneration. APOE-mediated neurodegenerative microglia led to a loss in their tolerogenic function. Taken together, our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target to restore homeostatic microglia.

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We show that induced TSPO expression marks a pro-inflammatory brain environment that is not necessarily accompanied by neuronal loss.

Currently CAD-CAM systems are rapidly gaining importance in dental practice as some of their products aim to combine aesthetics with strength and are free of metals. This study reports on the crown adaptation, marginal fit and clinical behaviour of 300 all-ceramic full coverage restorations (Procera, Gothenburg, Sweden) placed in one clinical centre and followed up to 5 years. The marginal fit and coping adaptation before and after luting was determined by direct measurement as well as after sectioning in a laboratory study. Three hundred all-ceram restorations were installed in 165 patients between 1994 and 1998. Before the end of 2000, patients were recalled to assess their restorations, using the California Dental Association quality evaluation index, their own appreciation, as well as the reaction towards the periodontium. The in vitro data revealed a mean marginal adaptation of 30 microm, before and after luting of the Al(2)0(3)-coping onto the tooth. However, at the deepest part of the chamfer, the distance increased to 135 microm. In the clinical study only one restoration fractured, while in 6% small porcelain infractions occurred. After polishing the latter, no persistent patient complaints remained. At the last recall visit 1.8% of the margins were rated unacceptable. Dentists rated 72 and 78% of the restorations excellent for surface, colour and anatomic form respectively. Eighty-seven per cent of the patients rated their restorations more than 7/10 on an ordered analogue scale for aesthetics as well as for function.