The gut microbiome plays an important role in immune function and has been implicated in several autoimmune disorders. Here we use 16S rRNA sequencing to investigate the gut microbiome in subjects with multiple sclerosis (MS,n=60) and healthy controls (n=43). Microbiome alterations in MS include increases inMethanobrevibacterandAkkermansiaand decreases inButyricimonas, and correlate with variations in the expression of genes involved in dendritic cell maturation, interferon signalling and NF-kB signalling pathways in circulating T cells and monocytes. Patients on disease-modifying treatment show increased abundances ofPrevotellaandSutterella, and decreasedSarcina, compared with untreated patients. MS patients of a second cohort show elevated breath methane compared with controls, consistent with our observation of increased gutMethanobrevibacterin MS in the first cohort. Further study is required to assess whether the observed alterations in the gut microbiome play a role in, or are a consequence of, MS pathogenesis.

Microglia activated by extracellularly deposited amyloid β peptide (Aβ) act as a two-edged sword in Alzheimer’s disease pathogenesis: on the one hand, they damage neurons by releasing neurotoxic proinflammatory mediators (M1 activation); on the other hand, they protect neurons by triggering anti-inflammatory/neurotrophic M2 activation and by clearing Aβ via phagocytosis. TLRs are associated with Aβ-induced microglial inflammatory activation and Aβ internalization, but the mechanisms remain unclear. In this study, we used real-time surface plasmon resonance spectroscopy and conventional biochemical pull-down assays to demonstrate a direct interaction between TLR2 and the aggregated 42-aa form of human Aβ (Aβ42). TLR2 deficiency reduced Aβ42-triggered inflammatory activation but enhanced Aβ phagocytosis in cultured microglia and macrophages. By expressing TLR2 in HEK293 cells that do not endogenously express TLR2, we observed that TLR2 expression enabled HEK293 cells to respond to Aβ42. Through site-directed mutagenesis of tlr2 gene, we identified the amino acids EKKA (741–744) as a critical cytoplasmic domain for transduction of inflammatory signals. By coexpressing TLR1 or TLR6 in TLR2-transgenic HEK293 cells or silencing tlrs genes in RAW264.7 macrophages, we observed that TLR2-mediated Aβ42-triggered inflammatory activation was enhanced by TLR1 and suppressed by TLR6. Using bone marrow chimeric Alzheimer’s amyloid precursor transgenic mice, we observed that TLR2 deficiency in microglia shifts M1- to M2-inflammatory activation in vivo, which was associated with improved neuronal function. Our study demonstrated that TLR2 is a primary receptor for Aβ to trigger neuroinflammatory activation and suggested that inhibition of TLR2 in microglia could be beneficial in Alzheimer’s disease pathogenesis.

Amyloid β (Aβ) damages neurons and triggers microglial inflammatory activation in the Alzheimer disease (AD) brain. BACE1 is the primary enzyme in Aβ generation. Neuroinflammation potentially up-regulates BACE1 expression and increases Aβ production. In Alzheimer amyloid precursor protein-transgenic mice and SH-SY5Y cell models, we specifically knocked out or knocked down gene expression of mapk14, which encodes p38α MAPK, a kinase sensitive to inflammatory and oxidative stimuli. Using immunological and biochemical methods, we observed that reduction of p38α MAPK expression facilitated the lysosomal degradation of BACE1, decreased BACE1 protein and activity, and subsequently attenuated Aβ generation in the AD mouse brain. Inhibition of p38α MAPK also enhanced autophagy. Blocking autophagy by treating cells with 3-methyladenine or overexpressing dominant-negative ATG5 abolished the deficiency of the p38α MAPK-induced BACE1 protein reduction in cultured cells. Thus, our study demonstrates that p38α MAPK plays a critical role in the regulation of BACE1 degradation and Aβ generation in AD pathogenesis.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease, in which activated microglia overexpressing ALS-linked SOD1 mutants (mSOD1) are known to contribute to neuronal death. However, it is unclear how mSOD1 expression affects micoglial activation and subsequently damages neurons. In this study, we created mSOD1-overexpressing BV-2 microglial cell lines. Following TLR2, but not TLR4 stimulation, we observed that overexpression of human SOD1 G93A, L8Q, or G10V mutant, as compared with the wild-type SOD1 or a mock control, significantly enhanced microglial secretion of a neurotoxic cytokine, tumor necrosis factor-alpha (TNF-alpha), which was dependent on the NADPH-oxidase-mediated increased generation of reactive oxygen species (ROS). In further experiments, we demonstrated that mSOD1 expression regulated TNF-alpha secretion at a post-transcriptional level and involved ROS-sensitive TNF-alpha-converting enzymes, e.g. ADAM10 and -17, which shed TNF-alpha from its membrane-anchored precursor. Together with a recent report that the function of SOD1, as a self-regulating redox sensor in NADPH oxidase-dependent ROS production, is lost due to its genetic mutations, we conclude that mSOD1 expression in ALS facilitates microglial neurotoxic inflammatory responses via TLR2, which is mediated by an uncontrolled ROS generation. The link, between mSOD1, innate immunity and NADPH oxidase, offers new opportunities in ALS therapies.