No abstract

Overall health has been linked to socioeconomic status, with the gap between social strata increasing each year. Studying the impact of social position on health and biological functioning in nonhuman primates has allowed researchers to model the human condition while avoiding ethical complexities or other difficulties characteristic of human studies. Using female cynomolgus macaques (Macaca fascicularis), our lab has examined the link between social status and stress for 30 years. Female nonhuman primates are especially sensitive to social stressors which can deleteriously affect reproductive health, leading to harmful consequences to their overall health. Subordinates have lower progesterone concentrations during the luteal phase of menstrual cycle, which is indicative of absence or impairment of ovulation. Subordinate animals receive more aggression, less affiliative attention, and are more likely to exhibit depressive behaviors. They also express higher stress-related biomarkers such as increased heart rates and lower mean cortisol. While no differences in body weight between dominant and subordinate animals are observed, subordinates have lower bone density and more visceral fat than their dominant counterparts. The latter increases risk for developing inflammatory diseases. Differences are also observed in neurological and autonomic function. A growing body of data suggests that diet composition may amplify or diminish physiological stress responses which have deleterious effects on health. More experimental investigation of the health effects of diet pattern is needed to further elucidate these differences in an ongoing search to find realistic and long-term solutions to the declining health of individuals living across the ever widening socioeconomic spectrum.

Currently there is no effective therapy available for cognitive impairments in Down syndrome (DS), one of the most prevalent forms of intellectual disability in humans associated with the chromosomes 21 trisomy. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that maintains glucose homeostasis by stimulating insulin secretion. Its natural cleavage product GLP-1 (9-36) lacks insulinotropic effects and has a low binding affinity for GLP-1 receptors; thus, GLP-1 (9-36) has historically been identified as an inactive metabolite. Conversely, recent work has demonstrated interesting physiological properties of GLP-1 (9-36) such as cardioprotection and neuroprotection. We have previously shown that GLP-1 (9-36) administration enhances neuronal plasticity in young WT mice and ameliorates cognitive deficits in a mouse model of Alzheimer’s disease. Here, we report that systemic administration of GLP-1 (9-36) in Ts65Dn DS model mice of either sex resulted in decreased mitochondrial oxidative stress in hippocampus and improved dendritic spine morphology, increase of mature spines and reduction of immature spines. Importantly, these molecular alterations translated into functional changes in that long-term potentiation failure and cognitive impairments in TsDn65 DS model mice were rescued with GLP-1 (9-36) treatment. We also show that chronic GLP-1 (9-36) treatment did not alter glucose tolerance in either WT or DS model mice. Our findings suggest that GLP-1 (9-36) treatment may have therapeutic potential for DS and other neurodegenerative diseases associated with increased neuronal oxidative stress.

No abstract

Synaptic dysfunction may represent an early and crucial pathophysiology in Alzheimer’s disease (AD). Recent studies implicate a connection between synaptic plasticity deficits and compromised capacity of de novo protein synthesis in AD. The mRNA translational factor eukaryotic elongation factor 1A (eEF1A) is critically involved in several forms of long-lasting synaptic plasticity. By examining postmortem human brain samples, a transgenic mouse model, and application of synthetic human Aβ42 on mouse hippocampal slices, we demonstrated that eEF1A protein levels were significantly decreased in AD, particularly in the hippocampus. In contrast, brain levels of eukaryotic elongation factor 2 were unaltered in AD. Further, upregulation of eEF1A expression by the adenylyl cyclase activator forskolin, which induces long-lasting synaptic plasticity, was blunted in hippocampal slices derived from Tg2576 AD model mice. Finally, Aβ-induced hippocampal long-term potentiation defects were alleviated by upregulation of eEF1A signaling via brain-specific knockdown of the gene encoding tuberous sclerosis 2. In summary, our findings suggest a strong correlation between the dysregulation of eEF1A synthesis and AD-associated synaptic failure. These findings provide insights into the understanding of molecular mechanisms underlying AD etiology and may aid in identification of novel biomarkers and therapeutic targets.