A human carboxypeptidase E/NF-α1 gene mutation in an Alzheimer's disease patient leads to dementia and depression in mice.

Patients with Alzheimer's disease (AD), a common dementia among the aging population, often also suffer from depression. This comorbidity is poorly understood. Although most forms of AD are not genetically inherited, we have identified a new human mutation in the carboxypeptidase E (CPE)/neurotrophic factor-α1 (NF-α1) gene from an AD patient that caused memory deficit and depressive-like behavior in transgenic mice. This mutation consists of three adenosine inserts, introducing nine amino acids, including two glutamines into the mutant protein, herein called CPE-QQ. Expression of CPE-QQ in Neuro2a cells demonstrated that it was not secreted, but accumulated in the endoplasmic reticulum and was subsequently degraded by proteasomes. Expression of CPE-QQ in rat hippocampal neurons resulted in cell death, through increased ER stress and decreased expression of pro-survival protein, BCL-2. Transgenic mice expressing CPE-QQ did not show any difference in the processing enzyme activity of CPE compared with wild-type mice. However, the transgenic mice exhibited poor memory, depressive-like behavior, severely decreased dendrites in the hippocampal CA3 region and medial prefrontal cortex indicative of neurodegeneration, hyperphosphorylation of tau at Ser396, and diminished neurogenesis in the dentate gyrus at 50 weeks old. All these pathologies are associated with AD and the latter with depression and were observed in 50-week-old mice. Interestingly, the younger CPE-QQ mice (11 weeks old) did not show deficits in dendrite outgrowth and neurogenesis. This study has uncovered a human CPE/NF-α1 gene mutation that could lead to comorbidity of dementia and depression, emphasizing the importance of this gene in cognitive function.

Effect of cold pressor test on the internal diameter of the radial artery.

The aim of this study was to investigate in normal subjects the effect of a cold pressor test on the caliber of the radial artery, a muscular artery of medium size. The internal diameter of this artery was measured continuously using a recently developed ultrasonic device. Immersion of one hand in ice water for two minutes increased blood pressure from 115/75 +/- 3/2 (Mean +/- SEM) to 136/90 +/- 6/2 mm Hg (P less than .001) and decreased the internal diameter of the radial artery from 2.82 +/- 0.12 to 2.60 +/- 0.09 mm (P less than .01). These data therefore indicate that the vasoconstriction induced by the cold pressor test involves not only arterioles, but also medium-size arteries.

Effect of vitamin E on carbonic anhydrase enzyme activity in rainbow trout (Oncorhynchus mykiss) erythrocytes in vitro and in vivo.

Considering that the excessive usage of vitamin E causes hypervitaminosis and thus reduces blood erythrocyte concentrations, therefore it is worth studying how its pharmacological dosage affects the activity of carbonic anhydrase (CA) enzyme found in erythrocytes of rainbow trout (Oncorhynchus mykiss) in vitro and in vivo. Vitamin E inhibited CA enzyme and the IC50 value of the vitamin was 0.039 mM in vitro. Similarly, it was seen that vitamin E inhibited CA enzyme activity after the first hour following vitamin E injections in vivo. The activities of CA in groups of trout given vitamin E injection were measured at 1, 3 and 5 h and the corresponding activities were found to be 772.7 +/- 290.5 (P < 0.05), 1286.4 +/- 378.2 and 1005.7 +/- 436.1 enzyme units (EU) g Hb(-1). The difference over the control was significant (P < 0.05) in the first hour and insignificant at 3 and 5 h (P > 0.05). The activity of CA in the control, which did not contain vitamin E, was determined as 1597.7 +/- 429.0 EU g Hb(-1).