In vivo micro computed tomography detection and decrease in amyloid load by using multifunctionalized gold nanorods: a neurotheranostic platform for Alzheimer's disease.

The development and use of nanosystems is an emerging strategy for the diagnosis and treatment of a broad number of diseases, such as Alzheimer's disease (AD). Here, we developed a neurotheranostic nanosystem based on gold nanorods (GNRs) that works as a therapeutic peptide delivery system and can be detected in vivo for microcomputed tomography (micro-CT), being a diagnostic tool. GNRs functionalized with the peptides Ang2 (a shuttle to the Central Nervous System) and D1 (that binds to the Aß peptide, also inhibiting its aggregation) allowed detecting differences in vivo between wild type and AD mice (APPswe/PSEN1dE9) 15 minutes after a single dose by micro-CT. Moreover, after a recurrent treatment for one month with GNRs-D1/Ang2, we observed a diminution of amyloid load and inflammatory markers in the brain. Thus, this new designed nanosystem exhibits promising properties for neurotheranostics of AD.

Connexin 43 hemichannels and pannexin-1 channels contribute to the α-synuclein-induced dysfunction and death of astrocytes.

Diverse studies have suggested that cytoplasmic inclusions of misfolded α-synuclein in neuronal and glial cells are main pathological features of different α-synucleinopathies, including Parkinson's disease and dementia with Lewy bodies. Up to now, most studies have focused on the effects of α-synuclein on neurons, whereas the possible alterations of astrocyte functions and neuron-glia crosstalk have received minor attention. Recent evidence indicates that cellular signaling mediated by hemichannels and pannexons is critical for astroglial function and dysfunction. These channels constitute a diffusional route of communication between the cytosol and the extracellular space and during pathological scenarios they may lead to homeostatic disturbances linked to the pathogenesis and progression of different diseases. Here, we found that α-synuclein enhances the opening of connexin 43 (Cx43) hemichannels and pannexin-1 (Panx1) channels in mouse cortical astrocytes. This response was linked to the activation of cytokines, the p38 MAP kinase, the inducible nitric oxide synthase, cyclooxygenase 2, intracellular free Ca2+ concentration ([Ca2+ ]i ), and purinergic and glutamatergic signaling. Relevantly, the α-synuclein-induced opening of hemichannels and pannexons resulted in alterations in [Ca2+ ]i dynamics, nitric oxide (NO) production, gliotransmitter release, mitochondrial morphology, and astrocyte survival. We propose that α-synuclein-mediated opening of astroglial Cx43 hemichannels and Panx1 channels might constitute a novel mechanism involved in the pathogenesis and progression of α-synucleinopathies.

Heavy Alcohol Exposure Activates Astroglial Hemichannels and Pannexons in the Hippocampus of Adolescent Rats: Effects on Neuroinflammation and Astrocyte Arborization.

A mounting body of evidence indicates that adolescents are specially more susceptible to alcohol influence than adults. However, the mechanisms underlying this phenomenon remain poorly understood. Astrocyte-mediated gliotransmission is crucial for hippocampal plasticity and recently, the opening of hemichannels and pannexons has been found to participate in both processes. Here, we evaluated whether adolescent rats exposed to ethanol exhibit changes in the activity of astrocyte hemichannels and pannexons in the hippocampus, as well as alterations in astrocyte arborization and cytokine levels. Adolescent rats were subjected to ethanol (3.0 g/kg) for two successive days at 48-h periods over 14 days. The opening of hemichannels and pannexons was examined in hippocampal slices by dye uptake, whereas hippocampal cytokine levels and astroglial arborization were determined by ELISA and Sholl analysis, respectively. We found that adolescent ethanol exposure increased the opening of connexin 43 (Cx43) hemichannels and pannexin-1 (Panx1) channels in astrocytes. Blockade of p38 mitogen-activated protein kinase (MAPK), inducible nitric oxide synthase (iNOS) and cyclooxygenases (COXs), as well as chelation of intracellular Ca2+, drastically reduced the ethanol-induced channel opening in astrocytes. Importantly, ethanol-induced Cx43 hemichannel and Panx1 channel activity was correlated with increased levels of interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), IL-6 in the hippocampus, as well as with profound alterations in astrocyte arbor complexity. Thus, we propose that uncontrolled opening of astrocyte hemichannels and pannexons may contribute not only to the glial dysfunction and neurotoxicity caused by adolescent alcohol consumption, but also to the pathogenesis of alcohol use disorders in the adulthood.

Scavenger Receptor-A deficiency impairs immune response of microglia and astrocytes potentiating Alzheimer's disease pathophysiology.

Late onset Alzheimer disease's (LOAD) main risk factor is aging. Although it is not well known which age-related factors are involved in its development, evidence points out to the involvement of an impaired amyloid-ß (Aß) clearance in the aged brain among possible causes. Glial cells are the main scavengers of the brain, where Scavenger Receptor class A (SR-A) emerges as a relevant player in AD because of its participation in Aß uptake and in the modulation of glial cell inflammatory response. Here, we show that SR-A expression is reduced in the hippocampus of aged animals and APP/PS1 mice. Given that Aß deposition increases in the aging brain, we generated a triple transgenic mouse, which accumulates Aß and is knockout for SR-A (APP/PS1/SR-A-/-) to evaluate Aß accumulation and the inflammatory outcome of SR-A depletion in the aged brain. The lifespan of APP/PS1/SR-A-/- mice was greatly reduced, accompanied by a 3-fold increase in plasmatic pro-inflammatory cytokines, and reduced performance in a working memory behavioral assessment. Microglia and astrocytes lacking SR-A displayed impaired oxidative response and nitric oxide production, produced up to 7-fold more pro-inflammatory cytokines and showed a 12-fold reduction in anti-inflammatory cytokines release, with conspicuous changes in lipopolysaccharide-induced glial activation. Isolated microglia from young and adult mice lacking SR-A showed a 50% reduction in phagocytic activity. Our results indicate that reduced expression of SR-A can deregulate glial inflammatory response and potentiate Aß accumulation, two mechanisms that could contribute to AD progression.

Microglia Function in the Normal Brain.

The activation of microglia has been recognized for over a century by their morphological changes. Long slender microglia acquire a short sturdy ramified shape when activated. During the past 20 years, microglia have been accepted as an essential cellular component for understanding the pathogenic mechanism of many brain diseases, including neurodegenerative diseases. More recently, functional studies and imaging in mouse models indicate that microglia are active in the healthy central nervous system. It has become evident that microglia release several signal molecules that play key roles in the crosstalk among brain cells, i.e., astrocytes and oligodendrocytes with neurons, as well as with regulatory immune cells. Recent studies also reveal the heterogeneous nature of microglia diverse functions depending on development, previous exposure to stimulation events, brain region of residence, or pathological state. Subjects to approach by future research are still the unresolved questions regarding the conditions and mechanisms that render microglia protective, capable of preventing or reducing damage, or deleterious, capable of inducing or facilitating the progression of neuropathological diseases. This novel knowledge will certainly change our view on microglia as therapeutic target, shifting our goal from their general silencing to the generation of treatments able to change their activation pattern.

Mycoplasmateceae species are not found in Fallopian tubes of women with tubo-peritoneal infertility.

BACKGROUND: The role of mycoplasmas on the development and sequelae of pelvic inflammatory disease remains controversial. The objective of the present study is to correlate directly the presence of Mycoplasmateceae through polimerase chain reaction (PCR) determinations in cervix and Fallopian tubes of infertile patients with tubo-peritoneal factor diagnosed through laparoscopy. METHODS: Thirty patients with tubo-peritoneal infertility and 30 normal fertile patients were included in the study; cervical samples and tubal flushings were obtained during laparoscopy. PCR determinations for the detection of genetic material of Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma urealiticum, Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis in cervix and tubal flushings were performed. RESULTS: No Mycoplasmataceae species as "only" microorganisms were found in tubal flushings of tubo-peritoneal infertility patients, whereas three (10%) fertile patients with normal tubes were positive for mycoplasma presence. This difference was not significant (p = 0.237). Among the 30 patients suffering from tubal infertility diagnosed through laparoscopy, Mycoplasmatecae species were not detected in the Fallopian tubes by PCR determinations, while in normal tubes from fertile patients these and other microorganisms could be found without distorting tubal anatomy. CONCLUSION: Mycoplasmateceae species were not detected in Fallopian tubes of women with tubo-peritoneal infertility.

Mycoplasmateceae species are not found in fallopian tubes of women with tubo-peritoneal infertility

BACKGROUND: The role of mycoplasmas on the development and sequelae of pelvic inflammatory disease remains controversial. The objective of the present study is to correlate directly the presence of Mycoplasmateceae through polimerase chain reaction (PCR) determinations in cervix and Fallopian tubes of infertile patients with tubo-peritoneal factor diagnosed through laparoscopy. METHODS: Thirty patients with tubo-peritoneal infertility and 30 normal fertile patients were included in the study; cervical samples and tubal flushings were obtained during laparoscopy. PCR determinations for the detection of genetic material of Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma urealiticum, Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis in cervix and tubal flushings were performed. RESULTS: No Mycoplasmataceae species as "only" microorganisms were found in tubal flushings of tubo-peritoneal infertility patients, whereas three (10%) fertile patients with normal tubes were positive for mycoplasma presence. This difference was not significant (p = 0.237). Among the 30 patients suffering from tubal infertility diagnosed through laparoscopy, Mycoplasmatecae species were not detected in the Fallopian tubes by PCR determinations, while in normal tubes from fertile patients these and other microorganisms could be found without distorting tubal anatomy. CONCLUSION: Mycoplasmateceae species were not detected in Fallopian tubes of women with tubo-peritoneal infertility.