Caspase-1 inhibition improves cognition without significantly altering amyloid and inflammation in aged Alzheimer disease mice.

Human genetic and animal model studies indicate that brain microglial inflammation is a primary driver of cognitive impairment in Alzheimer Disease (AD). Inflammasome-activated Caspase-1 (Casp1) is associated with both AD microglial inflammation and neuronal degeneration. In mice, Casp1 genetic ablation or VX-765 small molecule inhibition of Casp1 given at onset of cognitive deficits strongly supports the association between microglial inflammation and cognitive impairment.

Therapeutic potential of Nlrp1 inflammasome, Caspase-1, or Caspase-6 against Alzheimer disease cognitive impairment.

The sequential activation of Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing protein 1 (Nlrp1) inflammasome, Caspase-1 (Casp1), and Caspase-6 (Casp6) is implicated in primary human neuron cultures and Alzheimer Disease (AD) neurodegeneration. To validate the Nlrp1-Casp1-Casp6 pathway in vivo, the APP J20 AD transgenic mouse model was generated on either a Nlrp1, Casp1 or Casp6 null genetic background and mice were studied at 4-5 months of age. Episodic memory deficits assessed with novel object recognition were normalized by genetic ablation of Nlrp1, Casp1, or Casp6 in J20 mice.

Children with vesicoureteric reflux have joint hypermobility and occasional tenascin XB sequence variants.

Introduction: To consider alternative mechanisms that give rise to a refluxing ureterovesical junction (UVJ), we hypothesized that children with a common heritable urinary tract defect, vesicoureteric reflux (VUR), may have a defect in the extracellular matrix composition of the UVJ and other tissues that would be revealed by assessment of the peripheral joints. Hypermobile joints can arise from defects in the extracellular matrix within the joint capsule that affect proteins, including tenascin XB (TNXB).

Methods: We performed an observational study of children with familial and non-familial VUR to determine the prevalence of joint hypermobility, renal scarring, and DNA sequence variants in TNXB.

Heterozygous loss-of-function mutation in Odd-skipped related 1 () is associated with vesicoureteric reflux, duplex systems, and hydronephrosis.

Odd-skipped related 1 (Osr1) is a transcriptional repressor that plays critical roles in maintaining the mesenchymal stem cell population within the developing kidney. Here, we report that newborn pups with a heterozygous null mutation in exhibit a 21% incidence of vesicoureteric reflux and have hydronephrosis and urinary tract duplications. Newborn pups have a short intravesical ureter, resulting in a less competent ureterovesical junction which arises from a delay in urinary tract development.

Vesicoureteric reflux and reflux nephropathy: from mouse models to childhood disease.

Vesicoureteric reflux (VUR) is a common congenital urinary tract defect that predisposes children to recurrent kidney infections. Kidney infections can result in renal scarring or reflux nephropathy defined by the presence of chronic tubulo-interstitial inflammation and fibrosis that is a frequent cause of end-stage renal failure. The discovery of mouse models with VUR and with reflux nephropathy has provided new opportunities to understand the pathogenesis of these conditions and may provide insight on the genes and the associated phenotypes that need to be examined in human studies.