Peripheral Administration of the Kv1.3-Blocking Peptide HsTX1[R14A] Improves Cognitive Performance in Senescence Accelerated SAMP8 Mice.

Increased expression of the voltage-gated potassium channel Kv1.3 in activated microglia, and the subsequent release of pro-inflammatory mediators, are closely associated with the progression of Alzheimer's disease (AD). Studies have shown that reducing neuroinflammation through the non-selective blockade of microglial Kv1.3 has the potential to improve cognitive function in mouse models of familial AD. We have previously demonstrated that a potent and highly-selective peptide blocker of Kv1.3, HsTX1[R14A], not only entered the brain parenchyma after peripheral administration in a lipopolysaccharide (LPS)-induced mouse model of inflammation, but also significantly reduced pro-inflammatory mediator release from activated microglia. In this study, we show that microglial expression of Kv1.3 is increased in senescence accelerated mice (SAMP8), an animal model of sporadic AD, and that subcutaneous dosing of HsTX1[R14A] (1 mg/kg) every other day for 8 weeks provided a robust improvement in cognitive deficits in SAMP8 mice. The effect of HsTX1[R14A] on the whole brain was assessed using transcriptomics, which revealed that the expression of genes associated with inflammation, neuron differentiation, synapse function, learning and memory were altered by HsTX1[R14A] treatment. Further study is required to investigate whether these changes are downstream effects of microglial Kv1.3 blockade or a result of alternative mechanisms, including any potential effect of Kv1.3 blockade on other brain cell types. Nonetheless, these results collectively demonstrate the cognitive benefits of Kv1.3 blockade with HsTX1[R14A] in a mouse model of sporadic AD, demonstrating its potential as a therapeutic candidate for this neurodegenerative disease.

Recombinant LipL32 and LigA from Leptospira are unable to stimulate protective immunity against leptospirosis in the hamster model.

The major antigenic component of pathogenic Leptospira spp. is lipopolysaccharide (LPS). However, due to the specificity of the immune response generated towards LPS and the diversity in leptospiral LPS carbohydrate structure, current commercial vaccines stimulate protection only against homologous or closely related serovars. Vaccines that confer heterologous protection would enhance protection in vaccinated animals and reduce transmission to humans. Several studies have investigated the potential of various leptospiral outer membrane proteins to stimulate protective immunity against pathogenic Leptospira species. These include the surface-exposed lipoproteins LipL32 and LigA. However, consistent protection from infection has proved difficult to reproduce. In this study we assessed the protective capacity of recombinant LipL32, the six carboxy-terminal unique Ig-like repeat domains of LigA (LigANI) and a LipL32-LigANI fusion protein in hamsters against infection with Leptospira interrogans serovar Manilae. Despite all of the proteins eliciting antibody responses, none of the hamsters was protected against infection.