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Background Slowed clearance of amyloid β (Aβ) is believed to underlie the development of Aβ plaques that characterize Alzheimer’s disease (AD). Aβ is cleared in part by the glymphatic system, a brain-wide network of perivascular pathways that supports the exchange of cerebrospinal and brain interstitial fluid. Glymphatic clearance, or perivascular CSF-interstitial fluid exchange, is dependent on the astroglial water channel aquaporin-4 (AQP4) as deletion of Aqp4 in mice slows perivascular exchange, impairs Aβ clearance, and promotes Aβ plaque formation. Methods To define the role of AQP4 in human AD, we evaluated AQP4 expression and localization in a human post mortem case series. We then used the α-syntrophin ( Snta1 ) knockout mouse model which lacks perivascular AQP4 localization to evaluate the effect that loss of perivascular AQP4 localization has on glymphatic CSF tracer distribution. Lastly, we crossed this line into a mouse model of amyloidosis (Tg2576 mice) to evaluate the effect of AQP4 localization on amyloid β levels. Results In the post mortem case series, we observed that the perivascular localization of AQP4 is reduced in frontal cortical gray matter of subjects with AD compared to cognitively intact subjects. This decline in perivascular AQP4 localization was associated with increasing Aβ and neurofibrillary pathological burden, and with cognitive decline prior to dementia onset. In rodent studies, Snta1 gene deletion slowed CSF tracer influx and interstitial tracer efflux from the mouse brain and increased amyloid β levels. Conclusions These findings suggest that the loss of perivascular AQP4 localization may contribute to the development of AD pathology in human populations.

Auxin is a key coordinative signal required for many aspects of plant development and its levels are controlled by auxin metabolism and intercellular auxin transport. Here we find that a member of PIN auxin transporter family, PIN8 is expressed in male gametophyte of Arabidopsis thaliana and has a crucial role in pollen development and functionality. Ectopic expression in sporophytic tissues establishes a role of PIN8 in regulating auxin homoeostasis and metabolism. PIN8 co-localizes with PIN5 to the endoplasmic reticulum (ER) where it acts as an auxin transporter. Genetic analyses reveal an antagonistic action of PIN5 and PIN8 in the regulation of intracellular auxin homoeostasis and gametophyte as well as sporophyte development. Our results reveal a role of the auxin transport in male gametophyte development in which the distinct actions of ER-localized PIN transporters regulate cellular auxin homoeostasis and maintain the auxin levels optimal for pollen development and pollen tube growth. Plant hormones, such as auxin, coordinate plant development. In this study, an auxin transporter—PIN8—that is expressed in the male gametophyte of Arabidopsis thaliana , is found to regulate cellular homoeostasis and maintain optimal levels of auxin for pollen development.

Autism spectrum disorder (ASD) is the most commonly diagnosed neurodevelopmental disorder. Independent of neuronal dysfunction, ASD and its associated comorbidities have been linked to hypomyelination and oligodendroglial dysfunction. Additionally, the neuromodulator adenosine has been shown to affect certain ASD comorbidities and symptoms, such as epilepsy, impairment of cognitive function, and anxiety. Adenosine is both directly and indirectly responsible for regulating the development of oligodendroglia and myelination through its interaction with, and modulation of, several neurotransmitters, including glutamate, dopamine, and serotonin. In this review, we will focus on the recent discoveries in adenosine interaction with physiological and pathophysiological activities of oligodendroglia and myelination, as well as ASD-related aspects of adenosine actions on neuroprotection and neuroinflammation. Moreover, we will discuss the potential therapeutic value and clinical approaches of adenosine manipulation against hypomyelination in ASD.

Epileptogenesis is a common consequence of brain insults; however, the prevention or delay of the epileptogenic process remains an important unmet medical challenge. Overexpression of glycine transporter 1 (GlyT1) is proposed as a pathological hallmark in the hippocampus of patients with temporal lobe epilepsy, and we previously demonstrated in rodent epilepsy models that augmentation of glycine suppressed chronic seizures and altered acute seizure thresholds. In the present study we evaluated the effect of the GlyT1 inhibitor, sarcosine (aka N-methylglycine), on epileptogenesis and also investigated possible mechanisms. We developed a modified rapid kindling model of epileptogenesis in rats combined with seizure score monitoring to evaluate the antiepileptogenic effect of sarcosine. We used immunohistochemistry and Western blot analysis for the evaluation of GlyT1 expression and epigenetic changes of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in the epileptogenic hippocampi of rats, and further evaluated expression changes in enzymes involved in the regulation of DNA methylation, ten-eleven translocation methylcytosine dioxygenase 1 (TET1), DNA-methyltransferase 1 (DNMT1), and DNMT3a. Our results demonstrated: (i) experimental evidence that sarcosine (3g/kg, i.p. daily) suppressed kindling epileptogenesis in rats; (ii) the sarcosine-induced antiepileptogenic effect was accompanied by a suppressed hippocampal GlyT1 expression as well as a reduction of hippocampal 5mC levels and a corresponding increase in 5hmC; and (iii) sarcosine treatment caused differential expression changes of TET1 and DNMTs. Together, these findings suggest that sarcosine has unprecedented disease-modifying properties in a kindling model of epileptogenesis in rats, which was associated with altered hippocampal DNA methylation. Thus, manipulation of the glycine system is a potential therapeutic approach to attenuate the development of epilepsy.

Auxin transport, which is mediated by specialized influx and efflux carriers, plays a major role in many aspects of plant growth and development. AUXIN1 (AUX1) has been demonstrated to encode a high-affinity auxin influx carrier. In Arabidopsis thaliana, AUX1 belongs to a small multigene family comprising four highly conserved genes (i.e., AUX1 and LIKE AUX1 [LAX] genes LAX1, LAX2, and LAX3). We report that all four members of this AUX/LAX family display auxin uptake functions. Despite the conservation of their biochemical function, AUX1, LAX1, and LAX3 have been described to regulate distinct auxin-dependent developmental processes. Here, we report that LAX2 regulates vascular patterning in cotyledons. We also describe how regulatory and coding sequences of AUX/LAX genes have undergone subfunctionalization based on their distinct patterns of spatial expression and the inability of LAX sequences to rescue aux1 mutant phenotypes, respectively. Despite their high sequence similarity at the protein level, transgenic studies reveal that LAX proteins are not correctly targeted in the AUX1 expression domain. Domain swapping studies suggest that the N-terminal half of AUX1 is essential for correct LAX localization. We conclude that Arabidopsis AUX/LAX genes encode a family of auxin influx transporters that perform distinct developmental functions and have evolved distinct regulatory mechanisms.

Background Slowed clearance of amyloid [beta] (A[beta]) is believed to underlie the development of A[beta] plaques that characterize Alzheimer's disease (AD). A[beta] is cleared in part by the glymphatic system, a brain-wide network of perivascular pathways that supports the exchange of cerebrospinal and brain interstitial fluid. Glymphatic clearance, or perivascular CSF-interstitial fluid exchange, is dependent on the astroglial water channel aquaporin-4 (AQP4) as deletion of Aqp4 in mice slows perivascular exchange, impairs A[beta] clearance, and promotes A[beta] plaque formation. Methods To define the role of AQP4 in human AD, we evaluated AQP4 expression and localization in a human post mortem case series. We then used the [alpha]-syntrophin (Snta1) knockout mouse model which lacks perivascular AQP4 localization to evaluate the effect that loss of perivascular AQP4 localization has on glymphatic CSF tracer distribution. Lastly, we crossed this line into a mouse model of amyloidosis (Tg2576 mice) to evaluate the effect of AQP4 localization on amyloid [beta] levels. Results In the post mortem case series, we observed that the perivascular localization of AQP4 is reduced in frontal cortical gray matter of subjects with AD compared to cognitively intact subjects. This decline in perivascular AQP4 localization was associated with increasing A[beta] and neurofibrillary pathological burden, and with cognitive decline prior to dementia onset. In rodent studies, Snta1 gene deletion slowed CSF tracer influx and interstitial tracer efflux from the mouse brain and increased amyloid [beta] levels. Conclusions These findings suggest that the loss of perivascular AQP4 localization may contribute to the development of AD pathology in human populations. Keywords: Alzheimer's disease, Aquaporin-4, AQP4, [alpha]-Syntrophin, glymphatic, Amyloid [beta], Perivascular, Astrocyte

Nature Communications 3: Article number: 941 (2012); Published: 3 July 2012; Updated: 5 February 2013. This Article contains errors in Figs 1, 4, and Supplementary Fig. S6, for which we apologize. In Fig. 1b, the Col picture was inadvertently duplicated from the image below it. In addition, the legend should have defined the scale bar for panel e as 1 μm.

Auxin transport is essential for the architecture and development of erect plants. In a network of transporters directing auxin flows, ATP-Binding Cassette (ABC) transporters are a ubiquitous family of proteins that actively transport important substrates, including auxins, across the plasma membrane. ABCB1 and ABCB19 have been shown to account for the majority of rootward auxin transport, but residual fluxes to the root tip in Arabidopsis b1b19 double mutants implies the involvement of at least one additional auxin transporter in this process. Of specific interest, the severe dwarfism seen in abcb1abcb19 is strikingly reminiscent of that seen in mutants defective in the FK506-binding protein 42 (FKBP42), known as TWISTED DWARF1 (TWD1). FKBPs function in the maturation and stabilization of proteins, and biochemical evidence indicates that TWD1 functions in ABCB protein maturation and activation in particular. However, although b1b19 largely phenocopies twd1, the relative severity of the twd1 phenotype further suggests TWD1 activity may regulate the missing rootward auxin transporter. A broad screen including 12 ABCBs now reveals that ABCB11 acts in concert with ABCB1 and ABCB19 in long-distance transport, with an additional role in basipetal auxin transport in leaf tissues. Support for this conclusion comes from analyses of ABCB11 expression, ABCB11 protein localization and interaction, growth phenotypes of b11 single and abcb1b19b11 triple mutants, and auxin transport and accumulation mediated by ABCB11. The comparative analysis of the ABCB knock-out lines with twd1-3 now provides the means to deconvolute the relationship between auxin, ABCB transporters and FKBP42, as well as the mechanisms leading to the phenotypes seen in the abcb and twd1 mutants. My work thus concludes both that B11 mediates long-distance rootward auxin efflux and that such function by ABCB transporters is crucial to describing the twd phenotype. Future uses of this work include the possibility of customizing plant architecture through the manipulation of substrate specificity and transport directionality of ABCB transporters.