Progressive age-related impairment of cognitive behavior in APP23 transgenic mice.

Transgenic APP23 mice expressing human APP(751) with the K670N/M671L mutation, were compared at ages 3, 18 or 25 months to non-transgenic littermates in passive avoidance and in a small and large Morris maze. The task in the smaller pool habituated their flight response to the platform. Impairments in passive avoidance and small pool performance in APP23 mice were clearly age-related. In the larger Morris maze APP23 mice at all ages were impaired in latency and distance swum before finding the platform. Identical performance of 18-month APP23 and controls in a visible platform condition indicates that the Morris maze performance deficit was not due to sensory, motor or motivational alterations. At age 3 months both groups initially unexpectedly avoided the visible platform, suggesting that in young mice neophobia may contribute significantly to performance in cognitive tests. In conclusion, APP23 mice exhibit both early behavioral impairment in the large Morris maze as well as impairments in passive avoidance and small pool performance that are marked only in old age.

The eyeless mouse mutation (ey1) removes an alternative start codon from the Rx/rax homeobox gene.

The eyeless inbred mouse strain ZRDCT has long served as a spontaneous model for human anophthalmia and the evolutionary reduction of eyes that has occurred in some naturally blind mammals. ZRDCT mice have orbits but lack eyes and optic tracts and have hypothalamic abnormalities. Segregation data suggest that a small number of interacting genes are responsible, including at least one major recessive locus, ey1. Although predicted since the 1940s, these loci were never identified. We mapped ey1 to chromosome 18 using an F2 genome scan and there found a Met10-->Leu mutation in Rx/rax, a homeobox gene that is expressed in the anterior headfold, developing retina, pineal, and hypothalamus and is translated via a leaky scanning mechanism. The mutation affects a conserved AUG codon that functions as an alternative translation initiation site and consequently reduces the abundance of Rx protein. In contrast to a targeted Rx null allele, which causes anophthalmia, central nervous system defects, and neonatal death, the hypomorphic M10L allele is fully viable.

Localization of dysfunctional tight junctions in Salmonella enterica serovar typhimurium-infected epithelial layers.

Infection of polarized MDCK epithelial layers by Salmonella enterica serovar Typhimurium is accompanied by increased tight junction permeability and by contraction of perijunctional actinomyosin. We localized dysfunctional tight junctions in serovar Typhimurium-infected MDCK layers by imaging apical-basolateral intramembrane diffusion of fluorescent lipid and found that loss of the apical-basolateral diffusion barrier (tight junction fence function) was most marked in areas of prominent perijunctional contraction. The protein kinase inhibitor staurosporine prevented perijunctional contraction but did not reverse the effects of serovar Typhimurium on tight junction barrier function. Hence, perijunctional contraction is not required for Salmonella-induced tight junction dysfunction and this epithelial response to infection may be multifactorial.

[Age-dependent enzymatic changes in human cerebral cortex (author's transl)]. / Altersbedingte enzymatische Veränderungen im menschlichen Grosshirncortex.

Little information about the possible neurochemical-enzymatic changes occuring during aging of human brain is available. We, therefore, investigated the activity of various enzymes of human brains obtained at autopsy and covering a range from 19 to 91 years. Protein kinase, which mediates the information carried by the second messenger cAMP, does not show age-related changes of basal activity. Cyclic AMP-dependent activation of protein kinase remains nearly constant up to 60 years of life, but undergoes a distinct and progressive decline between 60 and 90 years. In corpus striatum no age-related changes of cyclic AMP-dependent protein kinase activity were observed. The activity of carbonic anhydrase demonstrates in both human cortex and corpus striatum an age-dependent decrease which also begins after the 6th decade of life. These neurochemical changes are similar to morphological and physiological changes occuring in the aging brain. They begin after the 60th year of life.