Differential Responses of Progesterone Receptor Membrane Component-1 (Pgrmc1) and the Classical Progesterone Receptor (Pgr) to 17β-Estradiol and Progesterone in Hippocampal Subregions that Support Synaptic Remodeling and Neurogenesis

Progesterone (P4) and estradiol (E2) modulate neurogenesis and synaptic remodeling in the hippocampus during the rat estrous cycle and in response to deafferenting lesions, but little is known about the steroidal regulation of hippocampal progesterone receptors associated with these processes. We examined the neuronal expression of progesterone receptor membrane component-1 (Pgrmc1) and the classical progesterone receptor (Pgr), by in situ hybridization and immunohistochemistry. Pgr, a transcription factor, has been associated with synaptic remodeling and other major actions of P4, whereas Pgrmc1 is implicated in P4-dependent proliferation of adult neuroprogenitor cells and with rapid P4 effects on membranes. Ovariectomized adult rats were given E2, P4, or E2+P4 on two schedules: a 4-d model of the rodent estrous cycle and a 30-d model of postmenopausal hormone therapy. Pgr was hormonally responsive only in CA1 pyramidal neurons, and the induction of Pgr by E2 was partly antagonized by P4 only on the 30-d schedule. In CA3 pyramidal and dentate gyrus (DG) neurons, Pgr was largely unresponsive to all hormone treatments. In contrast to Pgr, Pgrmc1 was generally induced by E2 and/or P4 throughout the hippocampus in CA1, CA3, and DG neurons. In neuroprogenitor cells of the DG (immunopositive for bromodeoxyuridine and doublecortin), both Pgrmc1 and Pgr were detected. The differential regulation of hippocampal Pgrmc1 and Pgr by E2 and P4 may guide drug development in hormonal therapy for support of neurogenesis and synaptic regeneration.This work was supported by National Institute on Aging Grants 1PO1 AG026572 (to R.D.B.); Project 4 (to C.E.F. and T.E.M.), Animal Core A (to T.E.M.), and Analytic Core C (to L.Z.)

Evaluations of tropospheric aerosol properties simulated by the community earth system model with a sectional aerosol microphysics scheme

A sectional aerosol model (CARMA) has been developed and coupled with the Community Earth System Model (CESM1). Aerosol microphysics, radiative properties, and interactions with clouds are simulated in the size-resolving model. The model described here uses 20 particle size bins for each aerosol component including freshly nucleated sulfate particles, as well as mixed particles containing sulfate, primary organics, black carbon, dust, and sea salt. The model also includes five types of bulk secondary organic aerosols with four volatility bins. The overall cost of CESM1-CARMA is approximately ∼2.6 times as much computer time as the standard three-mode aerosol model in CESM1 (CESM1-MAM3) and twice as much computer time as the seven-mode aerosol model in CESM1 (CESM1-MAM7) using similar gas phase chemistry codes. Aerosol spatial-temporal distributions are simulated and compared with a large set of observations from satellites, ground-based measurements, and airborne field campaigns. Simulated annual average aerosol optical depths are lower than MODIS/MISR satellite observations and AERONET observations by ∼32%. This difference is within the uncertainty of the satellite observations. CESM1/CARMA reproduces sulfate aerosol mass within 8%, organic aerosol mass within 20%, and black carbon aerosol mass within 50% compared with a multiyear average of the IMPROVE/EPA data over United States, but differences vary considerably at individual locations. Other data sets show similar levels of comparison with model simulations. The model suggests that in addition to sulfate, organic aerosols also significantly contribute to aerosol mass in the tropical UTLS, which is consistent with limited data

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 Alzheimer's disease. The ovarian sex steroid hormones 17β-estradiol (E2) and progesterone (P4) 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 E2 and P4 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 E2 and P4 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 Alzheimer's disease.This work was supported by National Institutes of Health Grant AG026572

Mammalian microtubule P-body dynamics are mediated by nesprin-1

Nesprins are a multi-isomeric family of spectrin-repeat (SR) proteins, predominantly known as nuclear envelope scaffolds. However, isoforms that function beyond the nuclear envelope remain poorly examined. Here, we characterize p50(Nesp1), a 50-kD isoform that localizes to processing bodies (PBs), where it acts as a microtubule-associated protein capable of linking mRNP complexes to microtubules. Overexpression of dominant-negative p50(Nesp1) caused Rck/p54, but not GW182, displacement from microtubules, resulting in reduced PB movement and cross talk with stress granules (SGs). These cells disassembled canonical SGs induced by sodium arsenite, but not those induced by hydrogen peroxide, leading to cell death and revealing PB–microtubule attachment is required for hydrogen peroxide-induced SG anti-apoptotic functions. Furthermore, p50(Nesp1) was required for miRNA-mediated silencing and interacted with core miRISC silencers Ago2 and Rck/p54 in an RNA-dependent manner and with GW182 in a microtubule-dependent manner. These data identify p50(Nesp1) as a multi-functional PB component and microtubule scaffold necessary for RNA granule dynamics and provides evidence for PB and SG micro-heterogeneity

Progesterone Influence on Neurite Outgrowth Involves Microglia

Progesterone (P4) antagonizes estradiol (E2) in synaptic remodeling in the hippocampus during the rat estrous cycle. To further understand how P4 modulates synaptic plasticity, we used entorhinal cortex lesions, which induce E2-dependent neurite sprouting in the hippocampus. In young ovariectomized rats, the E2-dependent entorhinal cortex lesion-induced sprouting was attenuated by concurrent treatment with P4 and E2. Microglial activation also showed the E2-P4 antagonism. These findings extend reports on the estrous cycle synaptic remodeling without lesions by showing the P4-E2 antagonism during simultaneous treatment with both E2 and P4. Glial mechanisms were analyzed with the wounding-in-a-dish model of cocultured glia and embryonic d-18 cortical neurons from rat. In cocultures of mixed glia (astrocytes plus 30% microglia), P4 antagonized the E2-dependent neurite outgrowth (number and length) and neuron viability in the presence of E2, as observed in vivo. However, removal of microglia (astrocyte-neuron coculture) abolished the antagonism of E2 by P4 on neuron sprouting. The P4 receptor antagonists ORG-31710 and RU-486 blocked the antagonism of P4 on E2-dependent sprouting. These findings suggest a new role for microglia in P4 antagonism of E2 in neuronal plasticity and show its dependence on progesterone receptors. These findings are also relevant to the inclusion of progestins in hormone therapy, which is controversial in relation to cognitive declines during aging and in Alzheimer’s disease

Erratum to: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (Autophagy, 12, 1, 1-222, 10.1080/15548627.2015.1100356

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