Anna M. Barron

Protective actions of sex steroid hormones in Alzheimer’s disease

Risk for Alzheimers disease (AD) is associated with age-related loss of sex steroid hormones in both women and men. In post-menopausal women, the precipitous depletion of estrogens and progestogens is hypothesized to increase susceptibility to AD pathogenesis, a concept largely supported by epidemiological evidence but refuted by some clinical findings. Experimental evidence suggests that estrogens have numerous neuroprotective actions relevant to prevention of AD, in particular promotion of neuron viability and reduction of beta-amyloid accumulation, a critical factor in the initiation and progression of AD. Recent findings suggest neural responsiveness to estrogen can diminish with age, reducing neuroprotective actions of estrogen and, consequently, potentially limiting the utility of hormone therapies in aged women. In addition, estrogen neuroprotective actions are also modulated by progestogens. Specifically, continuous progestogen exposure is associated with inhibition of estrogen actions whereas cyclic delivery of progestogens may enhance neural benefits of estrogen. In recent years, emerging literature has begun to elucidate a parallel relationship of sex steroid hormones and AD risk in men. Normal age-related testosterone loss in men is associated with increased risk to several diseases including AD. Like estrogen, testosterone has been established as an endogenous neuroprotective factor that not only increases neuronal resilience against AD-related insults, but also reduces beta-amyloid accumulation. Androgen neuroprotective effects are mediated both directly by activation of androgen pathways and indirectly by aromatization to estradiol and initiation of protective estrogen signaling mechanisms. The successful use of hormone therapies in aging men and women to delay, prevent, and or treat AD will require additional research to optimize key parameters of hormone therapy and may benefit from the continuing development of selective estrogen and androgen receptor modulators.

Sex hormones, aging, and Alzheimer's disease.

A promising strategy to delay and perhaps prevent Alzheimers disease (AD) is to identify the age-related changes that put the brain at risk for the disease. A significant normal age change known to result in tissue-specific dysfunction is the depletion of sex hormones. In women, menopause results in a relatively rapid loss of estradiol and progesterone. In men, aging is associated with a comparatively gradual yet significant decrease in testosterone. We review a broad literature that indicates age-related losses of estrogens in women and testosterone in men are risk factors for AD. Both estrogens and androgens exert a wide range of protective actions that improve multiple aspects of neural health, suggesting that hormone therapies have the potential to combat AD pathogenesis. However, translation of experimental findings into effective therapies has proven challenging. One emerging treatment option is the development of novel hormone mimetics termed selective estrogen and androgen receptor modulators. Continued research of sex hormones and their roles in the aging brain is expected to yield valuable approaches to reducing the risk of AD.

Ligand for Translocator Protein Reverses Pathology in a Mouse Model of Alzheimer's Disease

Ligands of the translocator protein (TSPO) elicit pleiotropic neuroprotective effects that represent emerging treatment strategies for several neurodegenerative conditions. To investigate the potential of TSPO as a therapeutic target for Alzheimers disease (AD), the current study assessed the effects of the TSPO ligand Ro5-4864 on the development of neuropathology in 3xTgAD mice. The effects of the TSPO ligand on neurosteroidogenesis and AD-related neuropathology, including β-amyloid accumulation, gliosis, and behavioral impairment, were examined under both early intervention (7-month-old young-adult male mice with low pathology) and treatment (24-month-old, aged male mice with advanced neuropathology) conditions. Ro5-4864 treatment not only effectively attenuated development of neuropathology and behavioral impairment in young-adult mice but also reversed these indices in aged 3xTgAD mice. Reduced levels of soluble β-amyloid were also observed by the combination of TSPO ligands Ro5-4864 and PK11195 in nontransgenic mice. These findings suggest that TSPO is a promising target for the development of pleiotropic treatment strategies for the management of AD.

Sex-specific effects of high fat diet on indices of metabolic syndrome in 3xTg-AD mice: implications for Alzheimer's disease.

Multiple factors of metabolic syndrome have been implicated in the pathogenesis of Alzheimers disease (AD), including abdominal obesity, insulin resistance, endocrine dysfunction and dyslipidemia. High fat diet, a common experimental model of obesity and metabolic syndrome, has been shown to accelerate cognitive decline and AD-related neuropathology in animal models. However, sex interacts with the metabolic outcomes of high fat diet and, therefore, may alter neuropathological consequences of dietary manipulations. This study examines the effects of sex and high fat diet on metabolic and AD-related neuropathological outcomes in 3xTg-AD mice. Three month-old male and female 3xTg-AD mice were fed either standard or high fat diets for 4 months. Obesity was observed in all high fat fed mice; however, ectopic fat accumulation, hyperglycemia and hyperinsulinemia were observed only in males. Interestingly, despite the different metabolic outcomes of high fat diet, the neuropathological consequences were similar: both male and female mice maintained under high fat diet exhibited significant worsening in behavioral performance and hippocampal accumulation of β-amyloid protein. Because high fat diet resulted in obesity and increased AD-like pathology in both sexes, these data support a role of obesity-related factors in promoting AD pathogenesis.

Age-related changes in neuroactive steroid levels in 3xTg-AD mice.

Although neuroactive steroids exert neuroprotective actions in different experimental models of neurodegenerative diseases, including those of Alzheimers disease (AD), their relationships with aged related physiologic and pathologic brain changes remain to be clarified. In this study the levels of pregnenolone, dehydroepiandrosterone, progesterone, dihydroprogesterone, tetrahydroprogesterone, isopregnanolone, testosterone, dihydrotestosterone, 5α-androstane-3α,17β-diol, 5α-androstane-3β,17β-diol, 17α-estradiol, and 17β-estradiol were assessed in the limbic region of young adult (7 months) and aged (24 months) male wild type and triple transgenic AD mice. Age related neuropathological changes in AD brains, such as β-amyloid accumulation and gliosis, were associated with modified levels of specific neuroactive steroids and particularly with changes in the levels of progesterone and testosterone metabolites. The altered levels of neuroactive steroids in aged AD brains might impact on the activation of neuroprotective signaling mediated by classic and nonclassic steroid receptors, like the gamma-aminobuttyric acid (GABA)-A receptor.

Prognostic indicators of 6-month mortality in elderly people with advanced dementia: A systematic review:

Background: For end-of-life dementia patients, palliative care offers a better quality of life than continued aggressive or burdensome medical interventions. To provide the best care options to dementia sufferers, validated, reliable, sensitive, and accurate prognostic tools to identify end-of-life dementia stages are necessary. Aim: To identify accurate prognosticators of mortality in elderly advanced dementia patients consistently reported in the literature. Design: Systematic literature review. Data sources: PubMed, Embase, and PsycINFO databases were searched up to September 2012. Reference lists of included studies were also searched. Inclusion criteria were studies measuring factors specifically related to 6-month outcome in patients diagnosed with dementia in any residential or health-care setting. Results: Seven studies met the inclusion criteria, five of which were set in the United States and two in Israel. Methodology and prognostic outcomes varied greatly between the studies. All but one study found that Functional Assessment Staging phase 7c, currently widely used to assess hospice admission eligibility in the United States, was not a reliable predictor of 6-month mortality. The most common prognostic variables identified related to nutrition/nourishment, or eating habits, followed by increased risk on dementia severity scales and comorbidities. Conclusions: Although the majority of studies agreed that the Functional Assessment Staging 7c criterion was not a reliable predictor of 6-month mortality, we found a lack of prognosticator concordance across the literature. Further studies are essential to identify reliable, sensitive, and specific prognosticators, which can be applied to the clinical setting and allow increased availability of palliative care to dementia patients.

Endogenous Synthesis of Corticosteroids in the Hippocampus

Background Brain synthesis of steroids including sex-steroids is attracting much attention. The endogenous synthesis of corticosteroids in the hippocampus, however, has been doubted because of the inability to detect deoxycorticosterone (DOC) synthase, cytochrome P450(c21). Methodology/Principal Findings The expression of P450(c21) was demonstrated using mRNA analysis and immmunogold electron microscopic analysis in the adult male rat hippocampus. DOC production from progesterone (PROG) was demonstrated by metabolism analysis of 3H-steroids. All the enzymes required for corticosteroid synthesis including P450(c21), P450(2D4), P450(11β1) and 3β-hydroxysteroid dehydrogenase (3β-HSD) were localized in the hippocampal principal neurons as shown via in situ hybridization and immunoelectron microscopic analysis. Accurate corticosteroid concentrations in rat hippocampus were determined by liquid chromatography-tandem mass spectrometry. In adrenalectomized rats, net hippocampus-synthesized corticosterone (CORT) and DOC were determined to 6.9 and 5.8 nM, respectively. Enhanced spinogenesis was observed in the hippocampus following application of low nanomolar (10 nM) doses of CORT for 1 h. Conclusions/Significance These results imply the complete pathway of corticosteroid synthesis of ‘pregnenolone →PROG→DOC→CORT’ in the hippocampal neurons. Both P450(c21) and P450(2D4) can catalyze conversion of PROG to DOC. The low nanomolar level of CORT synthesized in hippocampal neurons may play a role in modulation of synaptic plasticity, in contrast to the stress effects by micromolar CORT from adrenal glands.

Caspase activation contributes to astrogliosis

Caspases, a family of cysteine proteases, are widely activated in neurons and glia in the injured brain, a response thought to induce apoptosis. However, caspase activation in astrocytes following injury is not strongly associated with apoptosis. The present study investigates the potential role of caspase activation in astrocytes with another characteristic response to neural injury, astrogliosis. Caspase activity and morphological and biochemical indices of astrogliosis and apoptosis were assessed in (i) cultured neonatal rat astrocytes treated with astrogliosis-inducing stimuli (dibutryl cAMP, β-amyloid peptide), and (ii) cultures of adult rat hippocampal astrocytes generated from control and kainate-lesioned rats. The effects of broad spectrum and specific pharmacological caspase inhibitors were assessed on indicators of astrogliosis, including stellate morphology and expression of glutamine synthetase and fibroblast growth factor-2. Reactive neonatal and adult astrocytes demonstrated an increase in total caspase activity with a corresponding increase in the expression of active caspase-3 in the absence of cell death. Broad spectrum caspase inhibition with zVAD significantly attenuated increases in glutamine synthetase and fibroblast growth factor-2 in the reactive astrocytes. In the reactive neonatal astrocyte cultures, specific inhibition of caspases-3 and -11 also attenuated glutamine synthetase and fibroblast growth factor-2 expression, but did not reverse the morphological reactive phenotype. Astrogliosis is observed in all forms of brain injury and despite extensive study, its molecular triggers remain largely unknown. While previous studies have demonstrated active caspases in astrocytes following acute brain injury, here we present evidence functionally implicating the caspases in astrogliosis.

Steroidogenic abnormalities in translocator protein knockout mice and significance in the aging male

The translocator protein (TSPO) has been proposed to act as a key component in a complex important for mitochondrial cholesterol importation, which is the rate-limiting step in steroid hormone synthesis. However, TSPO function in steroidogenesis has recently been challenged by the development of TSPO knockout (TSPO-KO) mice, as they exhibit normal baseline gonadal testosterone and adrenal corticosteroid production. Here, we demonstrate that despite normal androgen levels in young male TSPO-KO mice, TSPO deficiency alters steroidogenic flux and results in reduced total steroidogenic output. Specific reductions in the levels of progesterone and corticosterone as well as age-dependent androgen deficiency were observed in both young and aged male TSPO-KO mice. Collectively, these findings indicate that while TSPO is not critical for achieving baseline testicular and adrenal steroidogenesis, either indirect effects of TSPO on steroidogenic processes, or compensatory mechanisms and functional redundancy, lead to subtle steroidogenic abnormalities which become exacerbated with aging.

Alzheimer’s disease: A journey from amyloid Peptides and Oxidative Stress, to Biomarker Technologies and Disease Prevention Strategies—Gains from AIBL and DIAN Cohort Studies

Worldwide there are over 46 million people living with dementia, and this number is expected to double every 20 years reaching about 131 million by 2050. The cost to the community and government health systems, as well as the stress on families and carers is incalculable. Over three decades of research into this disease have been undertaken by several research groups in Australia, including work by our original research group in Western Australia which was involved in the discovery and sequencing of the amyloid-β peptide (also known as Aβ or A4 peptide) extracted from cerebral amyloid plaques. This review discusses the journey from the discovery of the Aβ peptide in Alzheimer’s disease (AD) brain to the establishment of pre-clinical AD using PET amyloid tracers, a method now serving as the gold standard for developing peripheral diagnostic approaches in the blood and the eye. The latter developments for early diagnosis have been largely achieved through the establishment of the Australian Imaging Biomarker and Lifestyle research group that has followed 1,100 Australians for 11 years. AIBL has also been instrumental in providing insight into the role of the major genetic risk factor apolipoprotein E ɛ4, as well as better understanding the role of lifestyle factors particularly diet, physical activity and sleep to cognitive decline and the accumulation of cerebral Aβ.