Steroidogenic Acute Regulatory Protein (StAR): Evidence of Gonadotropin-Induced Steroidogenesis in Alzheimer Disease

BACKGROUND: Alzheimer disease (AD) is clinically characterized by progressive memory loss, impairments in behavior, language and visual-spatial skills and ultimately, death. Epidemiological data reporting the predisposition of women to AD has led to a number of lines of evidence suggesting that age-related changes in hormones of the hypothalamic-pituitary-gonadal (HPG) axis following reproductive senescence, may contribute to the etiology of AD. Recent studies from our group and others have reported not only increases in circulating gonadotropins, namely luteinizing hormone (LH) in individuals with AD compared with control individuals, but also significant elevations of LH in vulnerable neuronal populations in individuals with AD compared to control cases as well as the highest density of gonadotropin receptors in the brain are found within the hippocampus, a region devastated in AD. However, while LH is higher in AD patients, the downstream consequences of this are incompletely understood. To begin to examine this issue, here, we examined the expression levels of steroidogenic acute regulatory (StAR) protein, which regulates the first key event in steroidogenesis, namely, the transport of cholesterol into the mitochondria, and is regulated by LH through the cyclic AMP second messenger pathway, in AD and control brain tissue. RESULTS: Our data revealed that StAR protein was markedly increased in both the cytoplasm of hippocampal pyramidal neurons as well as in the cytoplasm of other non-neuronal cell types from AD brains when compared with age-matched controls. Importantly, and suggestive of a direct mechanistic link, StAR protein expression in AD brains colocalized with LH receptor expression. CONCLUSION: Therefore, our findings suggest that LH is not only able to bind to its receptor and induce potentially pathogenic signaling in AD, but also that steroidogenic pathways regulated by LH may play a role in AD

Early Induction of Oxidative Stress in Mouse Model of Alzheimer Disease with Reduced Mitochondrial Superoxide Dismutase Activity

While oxidative stress has been linked to Alzheimer's disease, the underlying pathophysiological relationship is unclear. To examine this relationship, we induced oxidative stress through the genetic ablation of one copy of mitochondrial antioxidant superoxide dismutase 2 (Sod2) allele in mutant human amyloid precursor protein (hAPP) transgenic mice. The brains of young (5–7 months of age) and old (25–30 months of age) mice with the four genotypes, wild-type (Sod2+/+), hemizygous Sod2 (Sod2+/−), hAPP/wild-type (Sod2+/+), and hAPP/hemizygous (Sod2+/−) were examined to assess levels of oxidative stress markers 4-hydroxy-2-nonenal and heme oxygenase-1. Sod2 reduction in young hAPP mice resulted in significantly increased oxidative stress in the pyramidal neurons of the hippocampus. Interestingly, while differences resulting from hAPP expression or Sod2 reduction were not apparent in the neurons in old mice, oxidative stress was increased in astrocytes in old, but not young hAPP mice with either Sod2+/+ or Sod2+/−. Our study shows the specific changes in oxidative stress and the causal relationship with the pathological progression of these mice. These results suggest that the early neuronal susceptibility to oxidative stress in the hAPP/Sod2+/− mice may contribute to the pathological and behavioral changes seen in this animal model

Fostering Aging in Place: Healthy Naturally Occurring Retirement Community (H-NORC) Qualities in a Southwest Ohio Suburb

This community assessment uses the concept of “H-NORCs” or Healthy Naturally Occurring Retirement Communities as a framework to analyze supports for aging (Masotti, Johnson-Masotti, Fick, & MacLeod, 2006) in Kettering, Ohio -- a first tier suburb of Dayton where the proportion of people over the age of 60 was 23.8% in 2010. In this study, I used focus groups and interviews to collect qualitative data on five H-NORC attributes: (1) economic policies that benefit seniors; (2) types of transportation support for seniors; (3) neighborhood design for physical activity; (4) opportunities for social integration and sense of belonging; and (5) health services. This study finds that Kettering is a regional support center for senior activity. City provision of senior services, volunteer opportunities, and regular exercise locations were perceived as protective of elder health and wellness. Participants perceived community outreach for citizens as a means of promoting health and longevity. Recent municipal projects demonstrate commitment toward improving neighborhoods to increase physical environment supports for aging in place according to H-NORC themes related to Universal design principles such as bicycle paths and sidewalk improvements. Still, it is important to note that although transportation services showed robust regular use by a small number of Kettering seniors, nearly all participants reported a lifelong relationship with driving that influences activity level and ability to participate in senior activities. Overall this study finds strong evidence of H-NORC qualities in Kettering related to economic policy benefits, sense of belonging, access to culture and service provision for seniors in the community. This study also suggests that H-NORC qualities related to physical supports in the built environment might be revised to more closely address Kettering’s suburban context

Systems-based practice to improve care within and beyond the emergency department

There is evidence that an emergency department (ED) visit signifies a period of vulnerability for older adults. Transition between the ED and community care can be fraught with challenges. There are essential elements for improved care transition from the ED to the community. Starting a new program requires buy-in from leaders, clinical team, and community. Improving care within an ED requires looking beyond the ED. Following implementation science will increase the success of program implementation and dissemination. There are successful alternative approaches that can be learned from when striving to improve care and transitions

Increased expression of p130 in Alzheimer disease

A number of recent findings support the notion of mechanistic parallels between Alzheimer disease (AD) and oncogenic processes, specifically, that neurons in AD, like cancer cells, display aberrant mitotic cell cycle re-entry. However, the mechanism that drives postmitotic neurons to reenter cell cycle remains elusive. In this study, we focused on the retinoblastoma-related protein p130 in AD. p130 is a transcriptional regulator that complexes with E2F4/5 in the nucleus and suppresses genes that regulate entry into the cell cycle. Interestingly, our results show that there are increases in p130 in cytoplasm of susceptible pyramidal neurons as well as neuroglia, often surrounding senile plaques, and within Hirano bodies in AD. By marked contrast, p130 is found at background levels in non-diseased, age-matched controls. Our data suggest that, despite its upregulation, the aberrant localization of p130 to the neuronal cytoplasm facilitates neuronal cell cycle re-entry in AD. © 2006 Springer Science+Business Media, LLC

Steroidogenic Acute Regulatory Protein (StAR): Evidence of Gonadotropin-Induced Steroidogenesis in Alzheimer Disease

Abstract Background Alzheimer disease (AD) is clinically characterized by progressive memory loss, impairments in behavior, language and visual-spatial skills and ultimately, death. Epidemiological data reporting the predisposition of women to AD has led to a number of lines of evidence suggesting that age-related changes in hormones of the hypothalamic-pituitary-gonadal (HPG) axis following reproductive senescence, may contribute to the etiology of AD. Recent studies from our group and others have reported not only increases in circulating gonadotropins, namely luteinizing hormone (LH) in individuals with AD compared with control individuals, but also significant elevations of LH in vulnerable neuronal populations in individuals with AD compared to control cases as well as the highest density of gonadotropin receptors in the brain are found within the hippocampus, a region devastated in AD. However, while LH is higher in AD patients, the downstream consequences of this are incompletely understood. To begin to examine this issue, here, we examined the expression levels of steroidogenic acute regulatory (StAR) protein, which regulates the first key event in steroidogenesis, namely, the transport of cholesterol into the mitochondria, and is regulated by LH through the cyclic AMP second messenger pathway, in AD and control brain tissue. Results Our data revealed that StAR protein was markedly increased in both the cytoplasm of hippocampal pyramidal neurons as well as in the cytoplasm of other non-neuronal cell types from AD brains when compared with age-matched controls. Importantly, and suggestive of a direct mechanistic link, StAR protein expression in AD brains colocalized with LH receptor expression. Conclusion Therefore, our findings suggest that LH is not only able to bind to its receptor and induce potentially pathogenic signaling in AD, but also that steroidogenic pathways regulated by LH may play a role in AD.</p

Neuronal HO-1 immunostaining in the pyramidal cells of the hippocampus of young (5–7 month-old) mice (A–D).

<p>Densitometric quantitation demonstrates that HO-1 levels tend to be higher in Sod2^+/− and hAPP/Sod2^+/− mice relative to mice with normal Sod2 levels (Sod^+/+ and hAPP/Sod2^+/+) (E). Bars represent the mean + SEM, n = 5−7 per group.</p

Sod2 reduction, in synergy with hAPP/Aβ expression, results in increased levels of the lipid peroxidation product HNE, in young (5–7 month-old) mice.

<p>Pyramidal neurons in the CA1 region of the hippocampus exhibit similar levels of HNE immunostaining in the hAPP-/Sod2^+/+ (A), hAPP-/Sod2^+/− (B), and the hAPP+/Sod2^+/+ (C) mice, whereas the hAPP+/Sod2^+/− mice exhibit increased levels of HNE (D). Quantification of the intensity of the neuronal HNE levels using densitometric analysis reveals the hAPP+/Sod2^+/− mice have significantly higher levels of neuronal HNE adducts as compared to hAPP+/Sod2^+/+, as well as the hAPP-/Sod2^+/+, hAPP-/Sod2^+/− mice (E). Bars represent mean + SEM, n = 5−7 per group *p<0.05, **p<0.01 by one-way ANOVA + Tukey Kramer post hoc analysis. ***p<0.05 by a one-tailed student's <i>t</i>-test.</p