DBA/2J Genetic Background Exacerbates Spontaneous Lethal Seizures but Lessens Amyloid Deposition in a Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is a leading cause of dementia in the elderly and is characterized by amyloid plaques, neurofibrillary tangles (NFTs) and neuronal dysfunction. Early onset AD (EOAD) is commonly caused by mutations in amyloid precursor protein (APP) or genes involved in the processing of APP including the presenilins (e.g. PSEN1 or PSEN2). In general, mouse models relevant to EOAD recapitulate amyloidosis, show only limited amounts of NFTs and neuronal cell dysfunction and low but significant levels of seizure susceptibility. To investigate the effect of genetic background on these phenotypes, we generated APP^swe and PSEN1^de9 transgenic mice on the seizure prone inbred strain background, DBA/2J. Previous studies show that the DBA/2J genetic background modifies plaque deposition in the presence of mutant APP but the impact of PSEN1^de9 has not been tested. Our study shows that DBA/2J.APP^swePSEN1^de9 mice are significantly more prone to premature lethality, likely to due to lethal seizures, compared to B6.APP^swePSEN1^de9 mice—70% of DBA/2J.APP^swePSEN1^de9 mice die between 2-3 months of age. Of the DBA/2J.APP^swePSEN1^de9 mice that survived to 6 months of age, plaque deposition was greatly reduced compared to age-matched B6.APP^swePSEN1^de9 mice. The reduction in plaque deposition appears to be independent of microglia numbers, reactive astrocytosis and complement C5 activity.     

Anteversion versus torsion of the femoral neck.

The usual term 'torsion angle of the femur' denotes the 'anteversion' of the neck of the femur as a whole, caused by the twist in the shaft of the femur rather than the twist in the neck. This has been differentiated from the twist in the neck of the femur around its own axis, termed 'torsion neck' and the values of both have been measured. To differentiate these two different phenomena, the term 'anteversion' is used to denote the usual angel described, while 'torsion neck' is sued to denote the twist in the neck around its own axis measured in this work. 1,000 femora from 21 cites in different parts of the country have been measured and the average anteversion angle calculated. The Indian average works out to be 12 degrees with a significantly (double) high value for females. The incidence of negative angle is 7% in the normal femora. All fractured femora invariably show a negative angle. The above information should be of great significance on orthopaedic surgery of the neck of the femur in these bones. The 'torsion neck' has been measured by tracing and its average reported as 30 degrees.     

Interaction of steroids with the nuclear envelope

Three approaches have been taken to determine the molecular mechanism by which steroid hormones traverse the nuclear envelope on their way to the genome. The first approach involved characterization of steroid binding to nuclear envelope preparations. We have characterized androgen binding to nuclear envelopes isolated from the rat ventral prostate, the rat liver, and androgen-responsive and androgen-unresponsive cell lines of the Shionogi mouse mammary carcinoma and glucocorticoid binding to rat liver. Relatively high affinity binding sites for steroids have been identified on nuclear envelopes. Importantly, the number and specificity of the sites correlates with the responsiveness of the tissue to the steroid. In the second approach, we have undertaken to identify the steroid binding site directly. As the characteristics of the rat ventral prostate site resembled those of the nuclear androgen receptor, we have begun purifying that receptor and have found fast protein liquid chromatography to be very effective. By affinity labelling studies, the dexamethasone binding site on the rat liver nuclear envelope has been identified as a peptide of molecular weight of approximately 90,000. The third approach we have used is to identify androgen-dependent peptides in nuclear envelope preparations. In both the rat ventral prostate and an androgen-responsive cell line of the Shionogi mouse mammary carcinoma, we have identified abundant androgen-dependent peptides. The relationship of these peptides to the binding sites identified by the first two approaches and their role in steroid transport is being investigated.     

Low frequency hereditary deafness in man with childhood onset.

A large kindred of hereditary deaf affected with a progressive sensorineural loss that begins during childhood with the low audiologic frequencies is described. Deafness progresses slowly through adolescence, when losses of up to 70 decibels are often detected. Affected adults present profound losses at all frequencies. Genetically, this deafness is transmitted as a simple, dominant, and autosomal mutation. No associated abnormalities have been detected in studies involving medical examinations, care histories, quantitation of several blood serum components, electrocardiograms, electrophoretograms, and karyotypes.     

Characterization of beta-adrenergic receptors in cultured human and bovine endothelial cells

We used radioligand binding methods to characterize beta-adrenergic receptors on endothelial cells cultured from adult human iliac vein (HIVE) and bovine fetal aorta (BFAE). For comparison, we also studied the well-characterized C6 glioma cell line (C6). Both human and bovine endothelial cells showed specific saturable binding of [125I]iodopindolol. There was no difference in the binding affinity (KD) of iodopindolol to membranes from the three cell types. However, the beta-receptor density (Bmax) was greater on HIVE cells and BFAE cells than on C6 cells. Displacement of ligand from HIVE and BFAE cells by zinterol or from BFAE cells by ICI 89,406 was consistent with binding to the beta 2-subtype. In contrast, displacement of ligand from C6 cells by zinterol or ICI 89,406 was consistent with binding to both beta 1- and beta 2-subtypes. Exposing BFAE cells in culture to 10 microM isoproterenol for 6 h resulted in a 55% decrease in Bmax without a change in KD. We conclude that 1) human and bovine endothelial cells in culture contain a substantial population of beta-adrenergic receptors, which are predominantly of the beta 2-subtype, and 2) endothelial beta-receptors exhibit downregulation by beta-agonists in culture.