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TAR DNA binding protein 43 kDa (TDP-43) plays an important role in several essential cell functions. However, TDP-43 dysfunction has been implicated in the development of various brain diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic predominant age-related TDP-43 encephalopathy (LATE). Recent investigations into the individual components of TDP-43 pathology show how broader TDP-43 dysfunction may precede these disease end states, and therefore could help to explain why TDP-43 dysfunction continues to be implicated in a rapidly expanding category of neurodegenerative diseases. The literature reviewed in this article suggests that dysregulation of TDP-43 initiated by some environmental and/or genetic insults can lead to a snowballing dysfunction across the cell, involving impaired gene expression, mRNA stability, as well as the function and coordination of those pathways directly regulated by TDP-43. Furthermore, the hallmarks of TDP-43 pathology, such as hyperphosphorylation and insoluble cytoplasmic accumulation of the protein may actually be artifacts of an upstream impairment in TDP-43’s normal function. Overall, the present article summarizes current knowledge regarding TDP-43’s normal and pathological cell functions and sheds light on possible mechanisms that underlie its causal role in neurodegeneration.

A major obstacle to progress in understanding the etiology of normative and pathological human brain aging is the availability of suitable animal models for experimentation. The present article will highlight our current knowledge regarding human brain aging and neurodegeneration, specifically in the context of Alzheimer’s disease (AD). Additionally, it will examine the use of the rhesus macaque monkey as a pragmatic translational animal model in which to study underlying causal mechanisms. Specifically, the discussion will focus on behavioral and protein-level brain changes that occur within the central nervous system (CNS) of aged monkeys, and compare them to the changes observed in humans during clinically normative aging and in AD.

CSF -klotho levels might affect Aβ40, Aβ42, and the Aβ42/40 ratio in the cerebrospinal fluid (CSF). CSF -klotho was assayed in ovariectomized rhesus macaques (NHPs) maintained on a Western-style diet (WSD) to assess the effect of estrogen hormone therapy (HT). CSF and serum -klotho was also analyzed in females and males of different ages and whether it was associated with Aβ42, Aβ40, or the Aβ42/40 ratio. Furthermore, CSF and serum -klotho were analyzed in women and men with dementia and controls and whether they were associated with CSF Aβ levels. HT was associated with increased CSF -klotho levels. Furthermore, -klotho and Aβ levels were correlated in a species- and cognitive health-dependent fashion. Higher CSF and serum levels of -klotho were seen in controls than in patients with dementia. Understanding the species differences in the beneficial effects of -klotho on CSF Aβ physiology should open new avenues for treating AD.

Amyloid beta (Aβ) plaque density was examined in the amygdala of rhesus macaques, to elucidate the influence of age, diet and hormonal environment. Luminex technology was used to measure cerebrospinal fluid (CSF) concentrations of Aβ and Aβ across three decades, while immunohistochemistry was used to examine Aβ plaque density in the amygdala. Aβ was found to be the predominant isoform of Aβ in the CSF, but neither Aβ or Aβ concentrations showed an age-related change, and the ratio of Aβ to Aβ showed only a marginal increase. Significantly fewer Aβ plaques were detected in the amygdala of old ovariectomized animals if they received estradiol HRT ( < 0.001); similar results were obtained regardless of whether they had been maintained on a regular monkey chow for ∼48 months or on a high-fat, high-sugar, Western-style diet for ∼30 months. The results demonstrate that HRT involving estrogen can reduce Aβ plaque load in a cognitive brain region of aged non-human primates. The results from this translational animal model may therefore have clinical relevance to the treatment of AD in post-menopausal women, whether used alone, or as a supplement to current pharmacological and monoclonal antibody-based interventions.

The hippocampus is especially susceptible to age-associated neuronal pathologies, and there is concern that the age-associated rise in cortisol secretion from the adrenal gland may contribute to their etiology. Furthermore, because 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) catalyzes the reduction of cortisone to the active hormone cortisol, it is plausible that an increase in the expression of this enzyme enhances the deleterious impact of cortisol in the hippocampus and contributes to the neuronal pathologies that underlie cognitive decline in the elderly. Rhesus macaques were used as a translational animal model of human aging, to examine age-related changes in gene and protein expressions of ( /HSD11B1) in the hippocampus, a region of the brain that plays a crucial role in learning and memory. Older animals showed significantly (  < 0.01) higher base-line cortisol levels in the circulation. In addition, they showed significantly (  < 0.05) higher hippocampal expression of but not and (i.e., two receptor-encoding genes through which cortisol exerts its physiological actions). A similar age-related significant (  < 0.05) increase in the expression of the HSD11B1 was revealed at the protein level by western blot analysis. The data suggest that an age-related increase in the expression of hippocampal is likely to raise cortisol concentrations in this cognitive brain area, and thereby contribute to the etiology of neuropathologies that ultimately lead to neuronal loss and dementia. Targeting this enzyme pharmacologically may help to reduce the negative impact of elevated cortisol concentrations within glucocorticoid-sensitive brain areas and thereby afford neuronal protection.

Background: The hypothalamus plays a key role in mediating the effects of estrogen on many physiological functions, including reproduction, metabolism, and thermoregulation. We have previously observed marked estrogen-dependent gene expression changes within the hypothalamus of rhesus macaques during aging, especially in the KNDy neurons of the arcuate-median eminence (ARC-ME) that produce kisspeptin, neurokinin B, and dynorphin A. Little is known, however, about the mechanisms involved in mediating the feedback from estrogen onto these neurons. Methods: We used quantitative real-time PCR to profile age- and estrogen-dependent gene expression changes in the rhesus macaque hypothalamus. Our focus was on genes that encode steroid receptors (ESR1, ESR2, PGR, and AR) and on enzymes that contribute to the local synthesis of 17β-estradiol (E 2 ; STS, HSD3B1/2, HSD17B5, and CYP19A). In addition, we used RT 2 Profiler™ PCR Arrays to profile a larger set of genes that are integral to hypothalamic function. Results: KISS1, KISS1R, TAC3, and NPY2R mRNA levels increased in surgically menopausal (ovariectomized) old females relative to age-matched ovariectomized animals that received E 2 hormone therapy. In contrast, PGR, HSD17B, GNRH2, SLC6A3, KISS1, TAC3, and NPY2R mRNA levels increased after E 2 supplementation. Conclusion: The rhesus macaque ARC-ME expresses many genes that are responsive to changes in circulating estrogen levels, even during old age, and these may contribute to causing the normal and pathophysiological changes that occur during menopause.

The beneficial effects of bioidentical ovarian steroid hormone therapy (HT) during the perimenopause are gaining recognition. However, the positive effects of estrogen (E) plus or minus progesterone (P) administration to ovariectomized (Ovx) lab animals were recognized in multiple systems for years before clinical trials could adequately duplicate the results. Moreover, very large numbers of women are often needed to find statistically significant results in clinical trials of HT; and there are still opposing results being published, especially in neural and cardiovascular systems. One of the obvious differences between human and animal studies is diet. Laboratory animals are fed a diet that is low in fat and refined sugar, but high in micronutrients. In the US, a large portion of the population eats what is known as a \"western style diet\" or WSD that provides calories from 36% fat, 44% carbohydrates (includes 18.5% sugars) and 18% protein. Unfortunately, obesity and diabetes have reached epidemic proportions and the percentage of obese women in clinical trials may be overlooked. We questioned whether WSD and obesity could decrease the positive neural effects of estradiol (E) in the serotonin system of old macaques that were surgically menopausal. Old ovo-hysterectomized female monkeys were fed WSD for 2.5 years, and treated with placebo, Immediate E (ImE) or Delayed E (DE). Compared to old Ovx macaques on primate chow and treated with placebo or E, the WSD-fed monkeys exhibited greater individual variance and blunted responses to E-treatment in the expression of genes related to serotonin neurotransmission, CRH components in the midbrain, synapse assembly, DNA repair, protein folding, ubiquitylation, transport and neurodegeneration. For many of the genes examined, transcript abundance was lower in WSD-fed than chow-fed monkeys. In summary, an obesogenic diet for 2.5 years in old surgically menopausal macaques blunted or increased variability in E-induced gene expression in the dorsal raphe. These results suggest that with regard to function and viability in the dorsal raphe, HT may not be as beneficial for obese women as normal weight women.

Whether glucocorticoids (GC) can directly affect human testicular functions is not well understood. A predominant site of GC receptor (GR; NR3C1) expression in the adult testis are peritubular smooth muscle-like cells, which express smooth muscle actin (ACTA2), contract and thereby are involved in sperm transport. In contrast to the adult, neither GR nor ACTA2, or elastin (ELN) were detected in the peritubular compartment before puberty in non-human primate testes. In isolated human testicular peritubular cells (HTPCs), activation of GR by dexamethasone (Dex) caused the translocation of GR to the nucleus and stimulated expression of ACTA2 and ELN, without affecting the expression of collagens. Cytoskeletal ACTA2-rearrangements were observed and were associated with an increased ability to contract. Our results indicate post-pubertal testicular roles of GC in the maintenance of the contractile, smooth muscle-like phenotype of peritubular cells.

Ischemia-reperfusion brain injury can be iatrogenically induced secondary to life-saving procedures. Prophylactic treatment of these patients offers a promising prevention for lifelong complications. We postulate that a cytosine-guanine (CpG) oligodeoxynucleotide (ODN) can provide robust antecedent protection against cerebral ischemic injury with minimal release of pro-inflammatory cytokines, making it an ideal candidate for further clinical development. Mouse and nonhuman primate (NHP) models of cerebral ischemic injury were used to test whether an A-type CpG ODN, which induces minimal systemic inflammatory cytokine responses, can provide prophylactic protection. Extent of injury in the mouse was measured by histological staining of live tissue. In the NHP, injury was assessed 2 and 7 days post-occlusion from T2-weighted magnetic resonance images and neurological and motor deficits were cataloged daily. Plasma cytokine levels were measured using species-specific Luminex assays. Prophylactic administration of an A-type CpG ODN provided robust protection against cerebral ischemic injury in the mouse with minimal systemic inflammation. Rhesus macaques treated with D192935, a mixture of human optimized A-type CpG ODNs, had smaller infarcts and demonstrated significantly less neurological and motor deficits following ischemic injury. Our findings demonstrate the translational potential of D192935 as a prophylactic treatment for patients at risk of cerebral ischemic injury.

Immunoassays have been the preferred method for steroid hormone analysis for more than 50 years. Automated immunoassays (AIAs) offer high throughput, rapid data turnaround, and low cost for measuring steroid hormone concentrations. The application of liquid chromatography–tandem mass spectrometry (LC-MS/MS) for steroid quantification provides greater specificity and selectivity for individual steroids, the ability to simultaneously analyze multiple steroids, and high throughput and automation. We compared AIA and LC-MS/MS for analysis of 17beta-estradiol (E2) and progesterone (P4) over the course of several menstrual cycles in 12 rhesus macaques (Macaca mulatta). Serum samples were collected every 4 days across four menstrual cycles from each monkey. AIAs were performed on a Roche cobas e411 analyzer. LC-MS/MS analysis was performed on a Shimadzu-Nexera-LCMS-8060 instrument. Scatter plots with Passing–Bablok regression showed excellent agreement between AIA and LC-MS/MS for both E2 and P4. Bland–Altman plots revealed no bias for either method; however, AIA overestimated E2 at concentrations >140 pg/ml and underestimated P4 at concentrations >4 ng/ml compared to LC-MS/MS. A comparison of testosterone concentrations measured by AIA and LC-MS/MS in the same samples was also performed. In contrast to E2 and P4, AIA and LC-MS/MS yielded significantly different results for testosterone concentrations, with AIA consistently underestimating concentrations relative to those obtained by LC-MS/MS. Well-characterized automated immunoassays are an excellent tool for daily monitoring of monkey menstrual cycles or providing single data points requiring fast turnaround. In certain situations where AIAs may provide inaccurate estimations of E2 and P4 concentrations, LC-MS/MS assays are preferable. Well-characterized automated immunoassays are an excellent tool for daily monitoring of monkey menstrual cycles or providing single data points requiring fast turnaround.