Anusha Jayaraman

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.

Progesterone inhibits estrogen-mediated neuroprotection against excitotoxicity by down-regulating estrogen receptor-β.

J. Neurochem. (2010) 115, 1277–1287.

Alzheimer’s Disease and Type 2 Diabetes: Multiple Mechanisms Contribute to Interactions

Obesity, metabolic syndrome, and type 2 diabetes (T2D) are related disorders with widespread deleterious effects throughout the body. One important target of damage is the brain. Persons with metabolic disorders are at significantly increased risk for cognitive decline and the development of vascular dementia and Alzheimer’s disease. Our review of available evidence from epidemiologic, clinical, and basic research suggests that neural dysfunction from T2D-related disease results from several underlying mechanisms, including metabolic, inflammatory, vascular, and oxidative changes. The relationships between T2D and neural dysfunction are regulated by several modifiers. We emphasize 2 such modifiers, the genetic risk factor apolipoprotein E and an age-related endocrine change, low testosterone. Both factors are independent risk factors for Alzheimer’s disease that may also cooperatively regulate pathologic interactions between T2D and dementia. Continued elucidation of the links between metabolic disorders and neural dysfunction promises to foster the development of effective therapeutic strategies.

Androgens Selectively Protect Against Apoptosis in Hippocampal Neurones

Androgens can protect neurones from injury, although androgen neuroprotection is not well characterised in terms of either specificity or mechanism. In the present study, we compared the ability of androgens to protect neurones against a panel of insults, empirically determined to induce cell death by apoptotic or non‐apoptotic mechanisms. Three criteria defining but not inclusive of apoptosis are: protection by caspase inhibition, protection by protein synthesis inhibition and the presence of pyknotic nuclei. According to these criteria, β‐amyloid, staurosporine, and Apoptosis Activator II induced cell death involving apoptosis, whereas hydrogen peroxide (H2O2), iron, calcium ionophore and 3‐nitropropionic acid induced cell death featuring non‐apoptotic characteristics. Pretreatment of hippocampal neurones with testosterone or dihydrotestosterone attenuated cell death induced by β‐amyloid, staurosporine and Apoptosis Activator II, but none of the other insults. The anti‐oxidant Trolox did not reduce cell death induced by β‐amyloid, staurosporine and Apoptosis Activator II, but did protect against H2O2 and iron. Similarly, a supra‐physiological concentration of oestrogen reduced cell death induced by H2O2 and iron, an effect not observed with androgens. We also show that activation of oestrogen pathways was not necessary for androgen neuroprotection. These data suggest that androgens directly activate a neuroprotective mechanism specific to inhibition of cell death involving apoptosis. Determining the specificity of androgen neuroprotection may enable the development of androgen compounds for the treatment of neurodegenerative disorders.

17β-estradiol and progesterone regulate expression of β-amyloid clearance factors in primary neuron cultures and female rat brain.

The accumulation of β-amyloid protein (Aβ) is a key risk factor in the development of Alzheimers disease. The ovarian sex steroid hormones 17β-estradiol (E(2)) and progesterone (P(4)) have been shown to regulate Aβ accumulation, although the underlying mechanism(s) remain to be fully elucidated. In this study, we investigate the effects of E(2) and P(4) treatment on the expression levels of Aβ clearance factors including insulin-degrading enzyme, neprilysin, endothelin-converting enzyme 1 and 2, angiotensin-converting enzyme, and transthyretin, both in primary neuron cultures and female rat brains. Our results show that E(2) and P(4) affect the expression levels of several Aβ clearance factors in dose- and time-dependent manners. Most notably, expression of insulin-degrading enzyme is significantly increased by both hormones in cultured neurons and in vivo and is inversely associated with the soluble Aβ levels in vivo. These findings further define sex steroid hormone actions involved in regulation of Aβ, a relationship potentially important to therapeutic approaches aimed at reducing risk of Alzheimers disease.

Progesterone Attenuates Oestrogen Neuroprotection Via Downregulation of Oestrogen Receptor Expression in Cultured Neurones

Recent findings indicate that progesterone can attenuate the beneficial neural effects of oestrogen. In the present study, we investigated the hypothesis that progesterone can modulate oestrogen actions by regulating the expression and activity of oestrogen receptors, ERα and ERβ. Our studies in cultured neurones demonstrate that progesterone decreases the expression of both ERα and ERβ and, as a consequence, also reduces both ER‐dependent transcriptional activity and neuroprotection. These results identify a potential mechanism by which progesterone antagonises neural oestrogen actions, a finding that may have important implications for hormone therapy in postmenopausal women.

Diet-induced obesity and low testosterone increase neuroinflammation and impair neural function

BackgroundLow testosterone and obesity are independent risk factors for dysfunction of the nervous system including neurodegenerative disorders such as Alzheimer’s disease (AD). In this study, we investigate the independent and cooperative interactions of testosterone and diet-induced obesity on metabolic, inflammatory, and neural health indices in the central and peripheral nervous systems.MethodsMale C57B6/J mice were maintained on normal or high-fat diet under varying testosterone conditions for a four-month treatment period, after which metabolic indices were measured and RNA isolated from cerebral cortex and sciatic nerve. Cortices were used to generate mixed glial cultures, upon which embryonic cerebrocortical neurons were co-cultured for assessment of neuron survival and neurite outgrowth. Peripheral nerve damage was determined using paw-withdrawal assay, myelin sheath protein expression levels, and Na+,K+-ATPase activity levels.ResultsOur results demonstrate that detrimental effects on both metabolic (blood glucose, insulin sensitivity) and proinflammatory (cytokine expression) responses caused by diet-induced obesity are exacerbated by testosterone depletion. Mixed glial cultures generated from obese mice retain elevated cytokine expression, although low testosterone effects do not persist ex vivo. Primary neurons co-cultured with glial cultures generated from high-fat fed animals exhibit reduced survival and poorer neurite outgrowth. In addition, low testosterone and diet-induced obesity combine to increase inflammation and evidence of nerve damage in the peripheral nervous system.ConclusionsTestosterone and diet-induced obesity independently and cooperatively regulate neuroinflammation in central and peripheral nervous systems, which may contribute to observed impairments in neural health. Together, our findings suggest that low testosterone and obesity are interactive regulators of neuroinflammation that, in combination with adipose-derived inflammatory pathways and other factors, increase the risk of downstream disorders including type 2 diabetes and Alzheimer’s disease.

Differential effects of synthetic progestagens on neuron survival and estrogen neuroprotection in cultured neurons

Progesterone and other progestagens are used in combination with estrogens for clinical purposes, including contraception and postmenopausal hormone therapy. Progesterone and estrogens have interactive effects in brain, however interactions between synthetic progestagens and 17β-estradiol (E2) in neurons are not well understood. In this study, we investigated the effects of seven clinically relevant progestagens on estrogen receptor (ER) mRNA expression, E2-induced neuroprotection, and E2-induced BDNF mRNA expression. We found that medroxyprogesterone acetate decreased both ERα and ERβ expression and blocked E2-mediated neuroprotection and BDNF expression. Conversely, levonorgestrel and nesterone increased ERα and or ERβ expression, were neuroprotective, and failed to attenuate E2-mediated increases in neuron survival and BDNF expression. Other progestagens tested, including norethindrone, norethindrone acetate, norethynodrel, and norgestimate, had variable effects on the measured endpoints. Our results demonstrate a range of qualitatively different actions of progestagens in cultured neurons, suggesting significant variability in the neural effects of clinically utilized progestagens.

Obesity and low testosterone interact to increase vulnerability to Alzheimer's disease pathogenesis

a possible role for c2orf40, an orphan gene that encodes Ecrg4, a 17,000 Dalton, secreted protein that has been previously associated with neural progenitor responsiveness after CNS injury, microglial activation in CNS tumors, and white matter senescence. Methods: Adult human cerebral cortical and choroid plexus tissue samples were obtained at autopsy. Ecrg4 gene expression in Alzheimer’s disease patients, cognitively normal, and disease age-matched controls was studied by quantitative RT PCR using the standard curve method. Processed protein forms were determined by Western blotting, and their distribution was examined in tissue sections using standard immunohistochemical staining techniques. Results: RT-qPCR demonstrated increased cerebral cortical Ecrg4 gene expression in AD, whereas similar analyses performed on frozen samples of choroid plexus showed no significant differences between AD and control. The peptide form of Ecrg4 detected in cortical gray matter of AD patients was a processed carboxy-terminal fragment of 8-10 kDa that was previously shown to interact with the innate immunity receptor complex. Immunocytochemical studies showed increased staining intensity in microglial cells and in intravascular blood-borne monocytes present within the cerebral cortical white matter of AD patients. Staining intensity appeared to be slightly diminished within cortical gray matter, except for prominent staining in rare neurofibrillary tangles. The staining pattern of the choroid plexus was similar in AD patients and controls, with robust immunoreactivity noted along the apical border of epithelial cells. Conclusions: Growing evidence suggests a role for Ecrg4 as an inflammatory mediator in microglial activation and as an initiator of oligodendrocyte precursor senescence. These data are the first to describe c2orf40 in the brain of Alzheimer’s disease patients and suggest that the Ecrg4 it encodes may participate in the activation and recruitment of microglial cells in cerebral white matter neuroinflammation.