Wilbur Song

TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques

Wang et al. report that TREM2 protects mice from Alzheimers disease by enabling resident microglia to insulate and alter Aβ plaque structure, thereby limiting neuritic damage.

Alzheimer's disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation

TREM2 is a lipid‐sensing activating receptor on microglia known to be important for Alzheimers disease (AD), but whether it plays a beneficial or detrimental role in disease pathogenesis is controversial.

IL-15 sustains IL-7R-independent ILC2 and ILC3 development

The signals that maintain tissue-resident innate lymphoid cells (ILC) in different microenvironments are incompletely understood. Here we show that IL-7 receptor (IL-7R) is not strictly required for the development of any ILC subset, as residual cells persist in the small intestinal lamina propria (siLP) of adult and neonatal Il7ra−/− mice. Il7ra−/− ILC2 primarily express an ST2− phenotype, but are not inflammatory ILC2. CCR6+ ILC3, which express higher Bcl-2 than other ILC3, are the most abundant subset in Il7ra−/− siLP. All ILC subsets are functionally competent in vitro, and are sufficient to provide enhanced protection to infection with C. rodentium. IL-15 equally sustains wild-type and Il7ra−/− ILC survival in vitro and compensates for IL-7R deficiency, as residual ILCs are depleted in mice lacking both molecules. Collectively, these data demonstrate that siLP ILCs are not completely IL-7R dependent, but can persist partially through IL-15 signalling.

Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism

Alzheimer’s disease (AD) is a neurodegenerative disease that causes late-onset dementia. The R47H variant of the microglial receptor TREM2 triples AD risk in genome-wide association studies. In mouse AD models, TREM2-deficient microglia fail to proliferate and cluster around the amyloid-&bgr; plaques characteristic of AD. In vitro, the common variant (CV) of TREM2 binds anionic lipids, whereas R47H mutation impairs binding. However, in vivo, the identity of TREM2 ligands and effect of the R47H variant remain unknown. We generated transgenic mice expressing human CV or R47H TREM2 and lacking endogenous TREM2 in the 5XFAD AD model. Only the CV transgene restored amyloid-&bgr;–induced microgliosis and microglial activation, indicating that R47H impairs TREM2 function in vivo. Remarkably, soluble TREM2 was found on neurons and plaques in CV- but not R47H-expressing 5XFAD brains, although in vitro CV and R47H were shed similarly via Adam17 proteolytic activity. These results demonstrate that TREM2 interacts with neurons and plaques duing amyloid-&bgr; accumulation and R47H impairs this interaction.

The Role of Surface Nonuniformity in Controlling the Initiation of a Galvanic Replacement Reaction

The use of silver nanocrystals--asymmetrically truncated octahedrons and nanobars--characterized by a nonuniform surface as substrates for a galvanic replacement reaction was investigated. As the surfaces of these nanocrystals contain facets with a variety of different areas, shapes, and atomic arrangements, we were able to examine the roles of these parameters in different stages of the galvanic replacement reaction with HAuCl(4) (e.g., pitting, hollowing, pit closing, and pore formation), and thus obtain a deeper understanding of the reaction mechanism than is possible with silver nanocubes. We found that the most important of these parameters was the atomic arrangement, that is, whether the surface was capped by a {100} or {111} facet, and that the area and shape of the facet had essentially no effect on the initiation of the reaction. Interestingly, through the reaction with asymmetrically truncated octahedrons, we were also able to demonstrate that even when pitting occurred over a large area, this region would be sealed through a combination of atomic diffusion and deposition during the intermediate stages of the reaction. Consequently, even if pitting occurred across a large percentage of the nanocrystal surface, it was still possible to maintain the morphology of the template throughout the reaction.

ApoE facilitates the microglial response to amyloid plaque pathology

One of the hallmarks of Alzheimer’s disease is the presence of extracellular diffuse and fibrillar plaques predominantly consisting of the amyloid-&bgr; (A&bgr;) peptide. Apolipoprotein E (ApoE) influences the deposition of amyloid pathology through affecting the clearance and aggregation of monomeric A&bgr; in the brain. In addition to influencing A&bgr; metabolism, increasing evidence suggests that apoE influences microglial function in neurodegenerative diseases. Here, we characterize the impact that apoE has on amyloid pathology and the innate immune response in APPPS1&Dgr;E9 and APPPS1-21 transgenic mice. We report that Apoe deficiency reduced fibrillar plaque deposition, consistent with previous studies. However, fibrillar plaques in Apoe-deficient mice exhibited a striking reduction in plaque compaction. Hyperspectral fluorescent imaging using luminescent conjugated oligothiophenes identified distinct A&bgr; morphotypes in Apoe-deficient mice. We also observed a significant reduction in fibrillar plaque–associated microgliosis and activated microglial gene expression in Apoe-deficient mice, along with significant increases in dystrophic neurites around fibrillar plaques. Our results suggest that apoE is critical in stimulating the innate immune response to amyloid pathology.

Immune Training Unlocks Innate Potential

Trained immunity is a form of innate immune memory with distinct features from classical adaptive immune memory. In the current issues of Cell and Cell Host & Microbe, five studies from the International Trained Immunity Consortium shed light on mechanisms and functional consequences of this phenomenon on cellular and whole-organism levels.

The Microglial Response to Neurodegenerative Disease

Microglia are a subset of tissue macrophages that constitute the major immune cell type of the central nervous system. These cells have long been known to change their morphology and functions in response to various neurological insults. Recently, a plethora of unbiased transcriptomics studies have revealed that across a broad spectrum of neurodegeneration-like disease models, microglia adopt a similar activation signature and perform similar functions. Despite these commonalities in response, the role of microglia has been described as both positive and negative in different murine disease models. In humans, genetic association studies have revealed strong connections between microglia genes and various neurodegenerative diseases, and mechanistic investigations of these mutations have added another layer of complexity. Here, we provide an overview of studies that have built a case for a common microglial response to neurodegeneration and discuss pathways that may be important to initiate and sustain this response; delineate the multifaceted functions of activated microglia spanning different diseases; and discuss insights from studying genes associated with disease in humans. We argue that strong evidence causally links activated microglia function to neurodegeneration and discuss what seems to be a conflict between mouse models and human genetics.

The identity and function of microglia in neurodegeneration

The predominant type of immune cell in the brain is the microglia, a type of tissue-resident macrophage. In a variety of neurodegenerative settings, microglia alter their transcriptional profile, morphology and function in similar ways; thus, these activated cells have been called ‘degeneration- or disease-associated microglia’ (DAM). These activated microglia can perform different functions and exert both positive effects and negative effects in different mouse disease models. In humans, mutations in genes expressed in microglia are linked to various neurodegenerative diseases. Here we provide an overview of the common microglial response to neurodegeneration and key contributing pathways; delineate the multifaceted functions of activated microglia spanning various diseases; and discuss insights from the study of human disease-associated genes. We argue that strong evidence from both mouse models and human genetics causally links the function of activated microglia to neurodegeneration.Song and Colonna provide an overview of the common microglial response to neurodegeneration and discuss insights from mouse models and the study of human disease-associated genes.

The Trem2 R47H Alzheimer’s risk variant impairs splicing and reduces Trem2 mRNA and protein in mice but not in humans

BackgroundThe R47H variant of the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) significantly increases the risk for late onset Alzheimer’s disease. Mouse models accurately reproducing phenotypes observed in Alzheimer’ disease patients carrying the R47H coding variant are required to understand the TREM2 related dysfunctions responsible for the enhanced risk for late onset Alzheimer’s disease.MethodsA CRISPR/Cas9-assisted gene targeting strategy was used to generate Trem2 R47H knock-in mice. Trem2 mRNA and protein levels as well as Trem2 splicing patterns were assessed in these mice, in iPSC-derived human microglia-like cells, and in human brains from Alzheimer’s patients carrying the TREM2 R47H risk factor.ResultsTwo independent Trem2 R47H knock-in mouse models show reduced Trem2 mRNA and protein production. In both mouse models Trem2 haploinsufficiency was due to atypical splicing of mouse Trem2 R47H, which introduced a premature stop codon. Cellular splicing assays using minigene constructs demonstrate that the R47H variant induced abnormal splicing only occurs in mice but not in humans. TREM2 mRNA levels and splicing patterns were both normal in iPSC-derived human microglia-like cells and patient brains with the TREM2 R47H variant.ConclusionsThe Trem2 R47H variant activates a cryptic splice site that generates miss-spliced transcripts leading to Trem2 haploinsufficiency only in mice but not in humans. Since Trem2 R47H related phenotypes are mouse specific and do not occur in humans, humanized TREM2 R47H knock-in mice should be generated to study the cellular consequences caused by the human TREM2 R47H coding variant. Currently described phenotypes of Trem2 R47H knock-in mice can therefore not be translated to humans.