Haploinsufficiency for Translation Elongation Factor eEF1A2 in Aged Mouse Muscle and Neurons Is Compatible with Normal Function

Translation elongation factor isoform eEF1A2 is expressed in muscle and neurons. Deletion of eEF1A2 in mice gives rise to the neurodegenerative phenotype "wasted" (wst). Mice homozygous for the wasted mutation die of muscle wasting and neurodegeneration at four weeks post-natal. Although the mutation is said to be recessive, aged heterozygous mice have never been examined in detail; a number of other mouse models of motor neuron degeneration have recently been shown to have similar, albeit less severe, phenotypic abnormalities in the heterozygous state. We therefore examined the effects of ageing on a cohort of heterozygous +/wst mice and control mice, in order to establish whether a presumed 50% reduction in eEF1A2 expression was compatible with normal function. We evaluated the grip strength assay as a way of distinguishing between wasted and wild-type mice at 3-4 weeks, and then performed the same assay in older +/wst and wild-type mice. We also used rotarod performance and immunohistochemistry of spinal cord sections to evaluate the phenotype of aged heterozygous mice. Heterozygous mutant mice showed no deficit in neuromuscular function or signs of spinal cord pathology, in spite of the low levels of eEF1A2

Expression of estrogen receptors in the hypothalamo-pituitary-ovarian axis in middle-aged rats after re-instatement of estrus cyclicity

During reproductive aging female rats enter an anovulatory state of persistent estrus (PE). In an animal model of re-instatement of estrus cyclicity in middle-aged PE rats we injected the animals with progesterone (0.5 mg progesterone/kg body weight) at 12:00 for 4 days whereas control animals received corn oil injections. After the last injection animals were analyzed at 13:00 and 17:00. Young regular cycling rats served as positive controls and were assessed at 13:00 and 17:00 on proestrus. Progesterone treatment of middle-aged PE rats led to occurrence of luteinizing hormone (LH), follicle stimulating hormone (FSH), and prolactin surges in a subset of animals that were denoted as responders. Responding middle-aged rats displayed a reduction of ER-β mRNA in the preoptic area which was similar to the effect in young rats. Within the mediobasal hypothalamus, only young rats showed a decline of ER-α mRNA expression. A decrease of ER-α mRNA levels in the pituitary was observed in progesterone-responsive rats and in young animals. ER-β mRNA expression was reduced in young regular cycling rats. ER-β mRNA levels in the ovary were reduced following progesterone treatment in PE rats and in young rats. Taken together our data show that cyclic administration of progesterone reinstates ovulatory cycles in intact aging females which have already lost their ability to display spontaneous cyclicity. This treatment leads to the occurrence of preovulatory LH, FSH and prolactin surges which are accompanied by differential modulation of ERs in the hypothalamus, the pituitary and the ovary

Translational models for vascular cognitive impairment: a review including larger species.

BACKGROUND: Disease models are useful for prospective studies of pathology, identification of molecular and cellular mechanisms, pre-clinical testing of interventions, and validation of clinical biomarkers. Here, we review animal models relevant to vascular cognitive impairment (VCI). A synopsis of each model was initially presented by expert practitioners. Synopses were refined by the authors, and subsequently by the scientific committee of a recent conference (International Conference on Vascular Dementia 2015). Only peer-reviewed sources were cited. METHODS: We included models that mimic VCI-related brain lesions (white matter hypoperfusion injury, focal ischaemia, cerebral amyloid angiopathy) or reproduce VCI risk factors (old age, hypertension, hyperhomocysteinemia, high-salt/high-fat diet) or reproduce genetic causes of VCI (CADASIL-causing Notch3 mutations). CONCLUSIONS: We concluded that (1) translational models may reflect a VCI-relevant pathological process, while not fully replicating a human disease spectrum; (2) rodent models of VCI are limited by paucity of white matter; and (3) further translational models, and improved cognitive testing instruments, are required

Translational animal models for Alzheimer's disease: An Alzheimer's Association Business Consortium Think Tank

Over 5 million Americans and 50 million individuals worldwide are living with Alzheimer\u27s disease (AD). The progressive dementia associated with AD currently has no cure. Although clinical trials in patients are ultimately required to find safe and effective drugs, animal models of AD permit the integration of brain pathologies with learning and memory deficits that are the first step in developing these new drugs. The purpose of the Alzheimer\u27s Association Business Consortium Think Tank meeting was to address the unmet need to improve the discovery and successful development of Alzheimer\u27s therapies. We hypothesize that positive responses to new therapies observed in validated models of AD will provide predictive evidence for positive responses to these same therapies in AD patients. To achieve this goal, we convened a meeting of experts to explore the current state of AD animal models, identify knowledge gaps, and recommend actions for development of next-generation models with better predictability. Among our findings, we all recognize that models reflecting only single aspects of AD pathogenesis do not mimic AD. Models or combinations of new models are needed that incorporate genetics with environmental interactions, timing of disease development, heterogeneous mechanisms and pathways, comorbidities, and other pathologies that lead to AD and related dementias. Selection of the best models requires us to address the following: (1) which animal species, strains, and genetic backgrounds are most appropriate; (2) which models permit efficient use throughout the drug development pipeline; (3) the translatability of behavioral-cognitive assays from animals to patients; and (4) how to match potential AD therapeutics with particular models. Best practice guidelines to improve reproducibility also need to be developed for consistent use of these models in different research settings. To enhance translational predictability, we discuss a multi-model evaluation strategy to de-risk the successful transition of pre-clinical drug assets to the clinic

Rotating-disk-type flow over loose boundaries

Rotating-disk-type flow of a liquid over a loose boundary, such as a layer of sand, is investigated. For this flow the formation of a new large-scale spiral pattern has been discovered. The new pattern is reminiscent of the Type-I spiral-vortex structures which characterize the laminar-turbulent transition region of boundary layers over rigid rotating disks. Flow visualizations reveal that the new pattern and the Type-I spiral vortices co-exist in the loose-boundary flow. The research investigating the origin of the new large-scale pattern is reviewed. Then photographs from flow visualizations are analysed to obtain estimates for the critical Reynolds number for which Type-I spiral vortices first appear for the loose-boundary flow and for the critical Reynolds numbers for the laminar-turbulent transition of the boundary layer. The results suggest that Type-I vortices appear at much lower Reynolds numbers over loose boundaries in comparison with flow over rigid rotating disks and that transition also appears to be advanced to much lower Reynolds numbers. The discussion of the results suggests that advanced transition arises from disturbances introduced into the flow after the loose boundary has been mobilized and not from disturbances associated with the roughness that the surfaces of the granular layer represents to the flow while grains are at rest

Age-related decreases in SYN levels associated with increases in MAP-2, apoE, and GFAP levels in the rhesus macaque prefrontal cortex and hippocampus

Loss of synaptic integrity in the hippocampus and prefrontal cortex (PFC) may play an integral role in age-related cognitive decline. Previously, we showed age-related increases in the dendritic marker microtubule associated protein 2 (MAP-2) and the synaptic marker synaptophysin (SYN) in mice. Similarly, apolipoprotein E (apoE), involved in lipid transport and metabolism, and glial fibrillary acidic protein (GFAP), a glia specific marker, increase with age in rodents. In this study, we assessed whether these four proteins show similar age-related changes in a nonhuman primate, the rhesus macaque. Free-floating sections from the PFC and hippocampus from adult, middle-aged, and aged rhesus macaques were immunohistochemically labeled for MAP-2, SYN, apoE, and GFAP. Protein levels were measured as area occupied by fluorescence using confocal microscopy as well as by Western blot. In the PFC and hippocampus of adult and middle-aged animals, the levels of SYN, apoE, and GFAP immunoreactivity were comparable but there was a trend towards higher MAP-2 levels in middle-aged than adult animals. There was significantly less SYN and more MAP-2, apoE, and GFAP immunoreactivity in the PFC and hippocampus of aged animals compared to adult or middle-aged animals. Thus, the age-related changes in MAP-2, apoE, and GFAP levels were similar to those previously observed in rodents. On the other hand, the age-related changes in SYN levels were not, but were similar to those previously observed in the aging human brain. Taken together, these data emphasize the value of the rhesus macaque as a pragmatic translational model for human brain aging