Clusterin (APOJ) in Alzheimer’s Disease: An Old Molecule with a New Role

Clusterin (CLU), initially identified in 1983 as a “clustering factor” in ram rete testis fluid, is a multifaceted protein that was re-discovered and subsequently renamed eight times from 1983 to 1992. CLU exists as multiple protein isoforms including the 80 kDa glycosylated mature/secreted form of CLU (mCLU) and the smaller non-modified nuclear and intracellular forms of CLU (nCLU and icCLU, respectively). These isoforms, which are expressed at the highest levels in the brain, are suggested to play distinct roles in various disease processes such as those involving inflammation and apoptosis. Currently, CLU, also known as apolipoprotein J (APOJ) which belongs to the same protein family as apolipoprotein E (APOE), is the third most significant genetic risk factor for the development of late-onset Alzheimer’s disease (LOAD); however, an extensive gap exists in the literature in understanding the physiological roles of CLU in normal brain and the pathogenic mechanisms conferred by CLU polymorphisms in the onset of LOAD. In this chapter, we discuss the status of the current knowledge regarding the generation and regulation of CLU protein isoforms, the clinical evidence and possible mechanisms involved in LOAD, and provide our perspectives for future studies

Estrogen receptor β in Alzheimer's disease: from mechanisms to therapeutics

Alzheimer's disease (AD) disproportionally affects women and men. The female susceptibility for AD has been largely associated with the loss of ovarian sex hormones during menopause. This review examines current understanding of the role of estrogen receptor β (ERβ) in the regulation of neurological health and its implication in the development and intervention of AD. Since its discovery in 1996, research conducted over the last 15-20 years has documented a great deal of evidence indicating that ERβ plays a pivotal role in a broad spectrum of brain activities from development to aging. ERβ genetic polymorphisms have been associated with cognitive impairment and increased risk for AD predominantly in women. The role of ERβ in the intervention of AD has been demonstrated by the alteration of AD pathology in response to treatment with ERβ-selective modulators in transgenic models that display pronounced plaque and tangle histopathological presentations as well as learning and memory deficits. Future studies that explore the potential interactions between ERβ signaling and the genetic isoforms of human apolipoprotein E (APOE) in brain aging and development of AD-risk phenotype are critically needed. The current trend of lost-in-translation in AD drug development that has primarily been based on early-onset familial AD (FAD) models underscores the urgent need for novel models that recapitulate the etiology of late-onset sporadic AD (SAD), the most common form of AD representing more than 95% of the current human AD population. Combining the use of FAD-related models that generally have excellent face validity with SAD-related models that hold more reliable construct validity would together increase the predictive validity of preclinical findings for successful translation into humans

Nuclear-receptor–mediated regulation of drug– and bile-acid–transporter proteins in gut and liver

This is an Accepted Manuscript of an article published by Taylor & Francis in Drug Metabolism Reviews on 2015 Sep 2, available online: http://www.tandfonline.com/10.3109/03602532.2012.748793.Adverse drug events (ADEs) are a common cause of patient morbidity and mortality and are classically thought to result, in part, from variation in expression and activity of hepatic enzymes of drug metabolism. It is now known that alterations in the expression of genes that encode drug- and bile-acid–transporter proteins in both the gut and liver play a previously unrecognized role in determining patient drug response and eventual clinical outcome. Four nuclear receptor (NR) superfamily members, including pregnane X receptor (PXR, NR1I2), constitutive androstane receptor (NR1I3), farnesoid X receptor (NR1H4), and vitamin D receptor (NR1I1), play pivotal roles in drug- and bile-acid– activated programs of gene expression to coordinately regulate drug- and bile-acid transport activity in the intestine and liver. This review focuses on the NR-mediated gene activation of drug and bile-acid transporters in these tissues as well as the possible underlying molecular mechanisms

Human ApoE ε2 promotes regulatory mechanisms of bioenergetic and synaptic function in female brain: a focus on V-type H+-ATPase

Humans possess three major isoforms of the apolipoprotein E (ApoE) gene encoded by three alleles: ApoE ε2 (ApoE2), ApoE ε3 (ApoE3), and ApoE ε4 (ApoE4). It is established that the three ApoE isoforms confer differential susceptibility to Alzheimer’s disease (AD); however, an in-depth molecular understanding of the underlying mechanisms is currently unavailable. In this study, we examined the cortical proteome differences among the three ApoE isoforms using 6-month-old female, human ApoE2, ApoE3, and ApoE4 gene-targeted replacement mice and two-dimensional proteomic analyses. The results reveal that the three ApoE brains differ primarily in two areas: cellular bioenergetics and synaptic transmission. Of particular significance, we show for the first time that the three ApoE brains differentially express a key component of the catalytic domain of the V-type H+-ATPase (Atp6v), a proton pump that mediates the concentration of neurotransmitters into synaptic vesicles and thus is crucial in synaptic transmission. Specifically, our data demonstrate that ApoE2 brain exhibits significantly higher levels of the B subunit of Atp6v (Atp6v1B2) when compared to both ApoE3 and ApoE4 brains, with ApoE4 brain exhibiting the lowest expression. Our additional analyses show that Atp6v1B2 is significantly impacted by aging and AD pathology and the data suggest that Atp6v1B2 deficiency could play a role in the progressive loss of synaptic integrity during early development of AD. Collectively, our findings indicate that human ApoE isoforms differentially modulate regulatory mechanisms of bioenergetic and synaptic function in female brain. A more efficient and robust status in both areas could serve as a potential mechanism contributing to the neuroprotective and cognition-favoring properties associated with the ApoE2 genotype

The CARMA correlator

The Combined Array for Research in Millimeter-wave Astronomy (CARMA) requires a flexible correlator to process the data from up to 23 telescopes and up to 8GHz of receiver bandwidth. The Caltech Owens Valley Broadband Reconfigurable Array (COBRA) correlator, developed for use at the Owens Valley millimeter-wave array and being used by the Sunyaev-Zeldovich Array (SZA), will be adapted for use by CARMA. The COBRA correlator system, a hybrid analog-digital design, consisting of downconverters, digitizers and correlators will be presented in this paper. The downconverters receive an input IF of 1-9GHz and produce a selectable output bandwidth of 62.5MHz, 125MHz, 250MHz, or 500MHz. The downconverter output is digitized at 1Gsample/s to 2-bits per sample. The digitized data is optionally digitally filtered to produce bands narrower than 62.5MHz (down to 2MHz). The digital correlator system is a lag- or XF-based system implemented using Field-Programmable Gate Arrays (FPGAs). The digital system implements delay lines, calculates the autocorrelations for each antenna, and the cross-correlations for each baseline. The number of lags, and hence spectral channels, produced by the system is a function of the input bandwidth; with the 500MHz band having the coarsest resolution, and the narrowest bandwidths having the finest resolution

A simultaneous search for prompt radio emission associated with the short GRB 170112A using the all-sky imaging capability of the OVRO-LWA

We have conducted the most sensitive low frequency (below 100 MHz) search to date for prompt, low-frequency radio emission associated with short-duration gamma-ray bursts (GRBs), using the Owens Valley Radio Observatory Long Wavelength Array (OVRO-LWA). The OVRO-LWA's nearly full-hemisphere field-of-view ($\sim20$,$000$ square degrees) allows us to search for low-frequency (sub-$100$ MHz) counterparts for a large sample of the subset of GRB events for which prompt radio emission has been predicted. Following the detection of short GRB 170112A by Swift, we used all-sky OVRO-LWA images spanning one hour prior to and two hours following the GRB event to search for a transient source coincident with the position of GRB 170112A. We detect no transient source, with our most constraining $1\sigma$ flux density limit of $650~\text{mJy}$ for frequencies spanning $27~\text{MHz}-84~\text{MHz}$. We place constraints on a number of models predicting prompt, low-frequency radio emission accompanying short GRBs and their potential binary neutron star merger progenitors, and place an upper limit of $L_\text{radio}/L_\gamma \lesssim 7\times10^{-16}$ on the fraction of energy released in the prompt radio emission. These observations serve as a pilot effort for a program targeting a wider sample of both short and long GRBs with the OVRO-LWA, including bursts with confirmed redshift measurements which are critical to placing the most constraining limits on prompt radio emission models, as well as a program for the follow-up of gravitational wave compact binary coalescence events detected by advanced LIGO and Virgo.Comment: 14 pages, 5 figures, ApJ submitte

Development of a Sideband Separation Receiver at 100 GHz

We have built and tested a prototype SIS receiver operating at 100 GHz to test the feasibility of sideband separation through quadrature mixing at millimeter and submillimeter wavelengths. We achieved over 40 dB of separation with no degradation of the mixer noise temperature due to the sideband separation. Both the sky signal and atmospheric noise are separated, greatly reducing the system temperature for millimeter and submillimeter observations in which spectral lines are present in only one sideband