Mycobacteria produce an unusual, glycolylated form of muramyl dipeptide (MDP) that is more potent and efficacious at inducing NOD2-mediated host responses. We tested the importance of this modified form of MDP in Mycobacterium tuberculosis by disrupting the gene, namH, responsible for this modification. In vitro, the namH mutant did not produce N-glycolylated muropeptides, but there was no alteration in colony morphology, growth kinetics, cellular morphology, or mycolic acid profile. Ex vivo, the namH mutant survived and replicated normally in murine and human macrophages, yet induced diminished production of tumor necrosis factor α. In vivo, namH disruption did not affect the bacterial burden during infection of C57BL/6 mice or cellular recruitment to the lungs but modestly prolonged survival after infection in Rag1(-/-) mice. These results indicate that the modified MDP is an important contributor to the unusual immunogenicity of mycobacteria but has a limited role in the pathogenesis of M. tuberculosis infection.

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Apolipoprotein E (ApoE) has become a primary focus of research after the discovery of its strong linkage to Alzheimer’s disease (AD), where the ApoE4 variant is the highest genetic risk factor for this disease. ApoE is commonly found in amyloid deposits of different origins, and its interaction with amyloid-β peptide (Aβ), the hallmark of AD, is well known. However, studies on the interaction of ApoEs with other amyloid-forming proteins are limited. Islet amyloid polypeptide (IAPP) is an amyloid-forming peptide linked to the development of type-2 diabetes and has also been shown to be involved in AD pathology and vascular dementia. Here we studied the impact of ApoE on IAPP aggregation and IAPP-induced toxicity on blood vessel pericytes. Using both in vitro and cell-based assays, we show that ApoE efficiently inhibits the amyloid formation of IAPP at highly substoichiometric ratios and that it interferes with both nucleation and elongation. We also show that ApoE protects the pericytes against IAPP-induced toxicity, however, the ApoE4 variant displays the weakest protective potential. Taken together, our results suggest that ApoE has a generic amyloid-interfering property and can be protective against amyloid-induced cytotoxicity, but there is a loss of function for the ApoE4 variant.

Amyloid-formation by the islet amyloid polypeptide (IAPP), produced by the β-cells in the human pancreas, has been associated with the development of type II diabetes mellitus (T2DM). The human plasma-protein transthyretin (TTR), a well-known amyloid-inhibiting protein, is interestingly also expressed within the IAPP producing β-cells. In the present study, we have characterized the ability of TTR to interfere with IAPP amyloid-formation, both in terms of its intrinsic stability as well as with regard to the effect of TTR-stabilizing drugs. The results show that TTR can prolong the lag-phase as well as impair elongation in the course of IAPP-amyloid formation. We also show that the interfering ability correlates inversely with the thermodynamic stability of TTR, while no such correlation was observed as a function of kinetic stability. Furthermore, we demonstrate that the ability of TTR to interfere is maintained also at the low pH environment within the IAPP-containing granules of the pancreatic β-cells. However, at both neutral and low pH, the addition of TTR-stabilizing drugs partly impaired its efficacy. Taken together, these results expose mechanisms of TTR-mediated inhibition of IAPP amyloid-formation and highlights a potential therapeutic target to prevent the onset of T2DM.

Alzheimer’s disease (AD) is strongly linked to amyloid depositions of the Aβ peptide (Aβ). The lipid‐binding protein apolipoprotein E (ApoE) has been found to interfere with Aβ amyloid formation and to exert a strong clinical impact to the pathology of AD. The APOE gene exists in three allelic isoforms represented by APOE ε2, APOE ε3, and APOE ε4. Carriers of the APOE ε4 variant display a gene dose‐dependent increased risk of developing the disease. Aβ amyloids are formed via a nucleation‐dependent mechanism where free monomers are added onto a nucleus in a template‐dependent manner. Using a combination of surface plasmon resonance and thioflavin‐T assays, we here show that ApoE can target the process of fibril elongation and that its interference effectively prevents amyloid maturation. We expose a complex equilibrium where the concentration of ApoE, Aβ monomers, and the amount of already formed Aβ fibrils will affect the relative proportion and formation rate of mature amyloids versus alternative assemblies. The result illustrates a mechanism which may affect both the clearance rate of Aβ assemblies in vivo and the population of cytotoxic Aβ assemblies.

Background Dizziness and vertigo affect around 15% of adults annually and represent common reasons for contacting health services, accounting for around 3% of all emergency department visits worldwide. Vertigo is also associated with excessive use of diagnostic imaging and emergency care and decreased productivity, primarily because of work absenteeism. Vestibular rehabilitation is an evidence-based treatment for chronic dizziness and supervised group exercise therapy has recently been shown to be effective after vestibular neuritis, a common cause of acute onset vertigo. However, such interventions are not readily available and there is a need for more easily accessible tools. The purpose of this study is to investigate the effects on vestibular symptoms of a 6-week online vestibular rehabilitation tool after acute onset vertigo, with the aim of aiding vestibular rehabilitation by presenting a more accessible tool that can help to reduce recovery time. Methods Three hundred twenty individuals diagnosed with acute vestibular syndrome (AVS) will be recruited from multiple hospitals in Sweden and the effects of an online vestibular rehabilitation tool, YrselTräning, on vestibular symptoms after acute onset vertigo will be compared to standard care (written instructions leaflet) in a two-armed, evaluator-blinded, multicenter randomized controlled trial. The primary outcome will be the Vertigo Symptom Scale Short Form (VSS-SF) score at 6 weeks after symptom onset. Secondary outcomes include effects of the intervention on activities of daily living, mood and anxiety, vestibular function recovery, mobility measures, health economic effects, and the reliability of the Swedish VSS-SF translation. Discussion Participants using the online vestibular rehabilitation tool are expected to recover earlier and to a greater extent from their symptoms as compared to standard care. Since up to 50% of people with AVS without treatment develop persistent symptoms, effective treatment of AVS will likely lead to a higher quality of life and help reduce the societal costs associated with dizziness and vertigo. Trial registration Clinicaltrials.gov NCT05056324. Registered on September 24, 2021.