Loss of GPR3 reduces the amyloid plaque burden and improves memory in Alzheimer's disease mouse models.

The orphan G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) GPR3 regulates activity of the γ-secretase complex in the absence of an effect on Notch proteolysis, providing a potential therapeutic target for Alzheimer's disease (AD). However, given the vast resources required to develop and evaluate any new therapy for AD and the multiple failures involved in translational research, demonstration of the pathophysiological relevance of research findings in multiple disease-relevant models is necessary before initiating costly drug development programs. We evaluated the physiological consequences of loss of Gpr3 in four AD transgenic mouse models, including two that contain the humanized murine Aß sequence and express similar amyloid precursor protein (APP) levels as wild-type mice, thereby reducing potential artificial phenotypes. Our findings reveal that genetic deletion of Gpr3 reduced amyloid pathology in all of the AD mouse models and alleviated cognitive deficits in APP/PS1 mice. Additional three-dimensional visualization and analysis of the amyloid plaque burden provided accurate information on the amyloid load, distribution, and volume in the structurally intact adult mouse brain. Analysis of 10 different regions in healthy human postmortem brain tissue indicated that GPR3 expression was stable during aging. However, two cohorts of human AD postmortem brain tissue samples showed a correlation between elevated GPR3 and AD progression. Collectively, these studies provide evidence that GPR3 mediates the amyloidogenic proteolysis of APP in four AD transgenic mouse models as well as the physiological processing of APP in wild-type mice, suggesting that GPR3 may be a potential therapeutic target for AD drug development.

Genetic modification of the inner ear lateral semicircular canal phenotype of the Bmp4 haplo-insufficient mouse.

In the mouse, development of the lateral semicircular canal of the inner ear is sensitive to Bmp4 heterozygosity. In the C57BL6 background 30% of the heterozygotes display circling behavior, 66% have a specific defect in the vestibular part of the inner ear, namely the constriction, interruption or absence of the lateral semicircular canal. Only mice having both ears affected display circling behavior. In the (C57BL6xCBA)N1 background, the penetrance of the canal phenotype is greatly reduced, and bilateral lateral canal defect is not sufficient to induce circling. We found association of the canal phenotype with the genotype of markers on chromosome 14 and 4, co-localizing with Ecs and Eclb identified in the Ecl mouse with similar lateral canal defects. Candidate genes to contain the causal mutation are Bmp4 on chromosome 14, and Rere on chromosome 4.

Vinblastine and doxorubicin administration to pregnant mice affects brain development and behaviour in the offspring.

BACKGROUND: Administration of chemotherapy during the fetal phase of pregnancy may put late-developing organs like the central nervous system at risk. METHODS: Transplacental transfer of doxorubicin and vinblastine was measured in C57/BJ mice by high-performance liquid chromatographic detection of the drugs in maternal and fetal plasma, 90 min after intravenous injection. Further, doxorubicin, vinblastine or saline were administered to pregnant C57/6J mouse dams on gestational day 17.5. Effects on brain morphology of the offspring were examined at 24h p.i. (immediate phase) and at 4-5 months p.i. (residual phase), using light- and electron microscopy. At the age of 3 months, offspring performed a behavioural test battery addressing neuromotor performance, exploration and anxiety, and learning and memory. RESULTS: Fetal plasma levels of doxorubicin and vinblastine reached respectively 5.0+/-0.2% and 13.9+/-2.4% of the maternal plasma levels. In the immediate phase, pathological examination revealed endothelial and perivascular parenchymal damage to the neocortical subventricular zone and a less constant thickening of the leptomeninx, in some cases also cortical lamination defects were noted. Brain histology was within normal limits in the mice of the residual phase group. Behavioural testing revealed subtle differences between drug-exposed and control mice. Grip strength was reduced in drug-exposed mice, but other tests for motor performance were normal. Several exploratory measures were altered, and there were some indications of increased anxiety in the drug-exposed mice. In the passive avoidance task, step-through latency was shorter in the drug-exposed mice, but their normal performance in the Morris water maze indicated that this was probably not due to impaired memory. CONCLUSION: The current preclinical data reveal subtle changes in behaviour and transiently also in brain morphology in the mice that were prenatally exposed to vinblastine or doxorubicin.

TBP as a candidate gene for mental retardation in patients with subtelomeric 6q deletions.

Monozygotic twin brothers with a subtelomeric 6q deletion presented with mental retardation, microcephaly, seizures, an enlarged cisterna magna, dimpling at elbows, a high arched palate and a thin upper lip. The same subtelomeric deletion was detected in the mother of the patients, presenting with a milder phenotype. We narrowed down the breakpoint to a region of approximately 100 kb and estimated the size of the terminal deletion to be 1.2 Mb. This region contains four known and seven putative genes. Comparison of the deletion with other reported patients showed TBP was the most plausible candidate gene for the mental retardation in this syndrome. We verified that the TBP gene expression was halved in our patients using real-time PCR. Cognitive and behavioural tests performed on previously described heterozygous tbp mice suggested that TBP is potentially involved in cognitive development.