KATP Channel Expression and Genetic Polymorphisms Associated with Progression and Survival in Amyotrophic Lateral Sclerosis.

The ATP-sensitive potassium (KATP) channel directly regulates the microglia-mediated inflammatory response following CNS injury. To determine the putative role of the KATP channel in amyotrophic lateral sclerosis (ALS) pathology, we investigated whether ALS induces changes in KATP channel expression in the spinal cord and motor cortex. We also characterized new functional variants of human ABCC8, ABCC9, KCNJ8, and KCNJ11 genes encoding for the KATP channel and analyzed their association with ALS risk, rate of progression, and survival in a Spanish ALS cohort. The expression of ABCC8 and KCNJ8 genes was enhanced in the spinal cord of ALS samples, and KCNJ11 increased in motor cortex of ALS samples, as determined by real-time polymerase chain reaction. We then sequenced the exons and regulatory regions of KATP channel genes from a subset of 28 ALS patients and identified 50 new genetic variants. For the case-control association analysis, we genotyped five selected polymorphisms with predicted functional relevance in 185 Spanish ALS (134 spinal ALS and 51 bulbar ALS) patients and 493 controls. We found that bulbar ALS patients presenting the G/G genotype of the rs4148646 variant of ABCC8 and the T/T genotype of the rs5219 variant of KCNJ11 survived longer than other ALS patients presenting other genotypes. Also, the C/C genotype of the rs4148642 variant of ABCC8 and the T/C genotype of the rs148416760 variant of ABCC9 modified the progression rate in spinal ALS patients. Our results suggest that the KATP channel plays a role in the pathophysiological mechanisms of ALS.

Amyloid-ß immunotherapy reduces amyloid plaques and astroglial reaction in aged domestic dogs.

BACKGROUND: Alzheimer's disease (AD) is characterized by the dynamic accumulation of extracellular amyloid deposits from the interplay between amyloid-ß (Aß) plaques, reactive astrocytes and activated microglia. Several immunotherapies against Aß have been shown to reduce amyloid neuropathology. However, the role of the associated glia in the recovery process requires clarification. Previously, we described the safety and effectiveness in aged domestic canine with cognitive dysfunction syndrome of a new active vaccine candidate for the treatment of AD in humans. OBJECTIVE: The aim of this article is to gain a better understanding of how immunotherapy modifies the amyloid burden and its effects on astroglial and microglial reactivity in immunized dogs. METHODS: In order to achieve this, we compared and quantified amyloid plaques and astroglial and microglial reactions in the frontal cortex of unimmunized and immunized aged domestic dogs. RESULTS: We found amyloid plaques from immunized dogs to be smaller and more compact than those from unimmunized dogs. In these new plaques, the associated astrocytes were closer and less immunoreactive to the ß subunit of S100 protein (S100B). We also found no modification in the microglial reaction associated with immunization. CONCLUSION: The anti-Aß immunotherapy developed in our laboratory modifies the equilibrium between soluble and insoluble Aß in aged dogs in close correlation with S100B-negative astrocytosis and microglial reaction.