Karin Dillner

Prolactin (PRL) Receptor Gene Expression in Mouse Adipose Tissue: Increases during Lactation and in PRL-Transgenic Mice

There are indications that PRL may exert important metabolic actions on adipose tissue in different species. However, with the exception of birds, the receptor has not been identified in white adipose tissue. The present study was designed to examine the possible expression and regulation of the PRL receptor (PRLR) in mouse adipose tissue. The long PRLR messenger RNA (mRNA) splice form (L-PRLR) and two short splice forms (S2- and S3-PRLR) were detected in mouse adipose tissue by RT-PCR. Furthermore, L-PRLR mRNA was detected by ribonuclease protection assay. Immunoreactive PRLR with a relative molecular mass of 95,000 was revealed by immunoblotting. Furthermore, L-PRLR mRNA expression was demonstrated in primary isolated adipocytes. In mouse adipose tissue, the level of L-PRLR mRNA expression increased 2.3-fold during lactation compared with those in virgin and pregnant mice. In contrast, in the liver the expression of L-PRLR increased 3.4-fold during pregnancy compared with those in virgin and lactating mice. When comparing the levels of L-PRLR expression in virgin female and male mice, no difference was detected in adipose tissue. However, in virgin female liver the expression was 4.5-fold higher than that in male liver. As PRL up-regulates its own receptor in some tissues, we analyzed L-PRLR expression in PRL-transgenic female and male mice. In PRL-transgenic mice L-PRLR expression was significantly increased in both adipose tissue (1.4-fold in females and 2.4-fold in males) and liver (1.9-fold in females and 2.7-fold in males) compared with that in control mice. Furthermore, in female PRL-transgenic mice retroperitoneal adipose tissue was decreased in weight compared with that in control mice. However, no difference was detected when comparing the masses of parametrial adipose tissue. Our results suggest a direct role for PRL, mediated by PRLR, in modulating physiological events in adipose tissue.

Progressive neuropathology and cognitive decline in a single Arctic APP transgenic mouse model

The Arctic APP mutation (E693G) leads to dementia with clinical features similar to Alzheimer disease (AD), but little is known about the pathogenic mechanism of this mutation. To address this question, we have generated a transgenic mouse model, TgAPParc, with neuron-specific expression of human APP with the Arctic mutation (hAPParc). Heterozygous mice from two separate founder lines with different levels of expression of hAPParc were analyzed with respect to brain morphology and behavior every 3 months until the age of 18 months. Standard histological stainings and immunohistochemistry using a panel of Aβ antibodies showed an age- and dose-dependant progression of amyloid deposition in the brain, starting in the subiculum and spreading to the thalamus. Cognitive behavioral testing revealed deficits in hippocampus-dependent spatial learning and memory in the Barnes maze test. This study demonstrates that the Arctic APP mutation is sufficient to cause amyloid deposition and cognitive dysfunction, and thus the TgAPParc mouse model provides a valuable tool to study the effect of the Arctic mutation in vivo without possible confounding effect of other APP mutations.

Gene Expression Studies of Prostate Hyperplasia in Prolactin Transgenic Mice

Benign prostatic hyperplasia (BPH) and prostate cancer are age-related diseases, affecting a majority of elderly men in the western world, and are known to be influenced by several different hormones, including sex hormones. Although the hormone prolactin (PRL) is well known to exert trophic effects on prostate cells, its involvement in pathophysiological conditions is still poorly characterized. In order to evaluate the potential role of PRL in promoting prostate growth, we have used a recently developed transgenic mouse model that overexpresses the PRL gene specifically in the prostate (Pb-PRL transgenic mice). The PRL transgenic mice develop a significant prostate hyperplasia which increases with age. The prostates of the Pb-PRL transgenic mice display a prominent stromal hyperplasia with mild epithelial dysplastic features, leading to an increased stromal/epithelial ratio. Accumulation of secretory material is also a major characteristic. By using cDNA microarray analysis we have obtained interesting insights into the molecular mechanisms involved in the prostate hyperplasia. Of particular interest is the significance of reduced apoptosis for the development/progression of the prostate phenotype. This finding was further confirmed by immunohistochemical analysis using two different apoptosis markers. Moreover, in line with the prominent expansion of the stromal compartment were the identified changes in gene expression seen in the PRL transgenic prostate, suggesting that activation of the stroma is important for the development of the prostate hyperplasia.

AbstractPoster presentation: Sunday posterP1-333: Genetic association to the novel CLAC gene in familial and clinic based Alzheimer’s disease cases

Background: One of the main pathological hallmarks of Alzheimer’s disease (AD) is the senile plaques mainly consistent of insoluble deposits of the amyloid peptide (A ). A number of other components have been identified to co-localize with senile plaques in the brains of AD patients. Recently, the novel collagenous Alzheimer amyloid plaque component (CLAC) was described. It shows a specific binding to A , implicating involvement of CLAC in A fibrillization, proteolysis protection and A -mediated cytotoxicity. The gene encoding CLAC is located on chromosome band 4q24-25, in a region where we have observed increased allele sharing in Swedish AD pedigrees. Objective(s): To investigate the potential role of CLAC as a susceptibility gene for AD. Methods: Association studies in two AD populations were performed: one containing familial AD (FAD) cases, the other made up of cases from the Memory Clinic at Karolinska University Hospital. A third, population based sample set is under investigation. Results: We observed significant association in FAD cases to four single nucleotide polymorphisms (SNPs) that are in linkage disequilibrium. Furthermore, the clinic based sample confirmed the association in two of the SNPs. Conclusions: Our results add genetic evidence to the previous experimental evidence for CLAC’s involvement in AD pathogenesis possibly by affecting the interaction between and CLAC.

P3-101: A unique gene expression signature discriminates familial Alzheimer’s disease mutation carriers from their wild type siblings

Alzheimers disease (AD) is a neurodegenerative disease with an insidious onset and progressive course that inevitably leads to death. The current diagnostic tools do not allow for diagnosis until the disease has lead to irreversible brain damage. Genetic studies of autosomal dominant early onset familial AD has identified three causative genes: amyloid precursor protein (APP), presenilin 1 and 2 (PSEN1 and PSEN2). We performed a global gene expression analysis on fibroblasts from 33 individuals (both healthy and demented mutation carriers as well as wild-type siblings) from three families segregating the APP(SWE), APP(ARC) and PSEN1 H163Y mutations, respectively. The mutations cause hereditary progressive cognitive disorder, including typical autosomal dominant AD. Our data show that the mutation carriers share a common gene expression profile significantly different from that of their wild-type siblings. The results indicate that the disease process starts several decades before the onset of cognitive decline, suggesting that presymptomatic diagnosis of AD and other progressive cognitive disorders may be feasible in the near future.