Almost all degenerative diseases of the CNS are associated with chronic inflammation. A central step in this process is the activation of brain mononuclear phagocyte cells, called microglia. While it is recognized that healthy neurons and astrocytes regulate the magnitude of microglia-mediated innate immune responses and limit excessive CNS inflammation, the endogenous signals governing this process are not fully understood. In the peripheral nervous system, recent studies suggest that an endogenous 'cholinergic anti-inflammatory pathway' regulates systemic inflammatory responses via a7 nicotinic acetylcholinergic receptors (nAChR) found on blood-borne macrophages. These data led us to investigate whether a similar cholinergic pathway exists in the brain that could regulate microglial activation. Here we report for the first time that cultured microglial cells express a7 nAChR subunit as determined by RT-PCR, western blot, immunofluorescent, and immunochistochemistry analyses. Acetylcholine and nicotine pre-treatment inhibit lipopolysaccharide (LPS)-induced TNF-a release in murine-derived microglial cells, an effect attenuated by a7 selective nicotinic antagonist, a-bungarotoxin. Furthermore, this inhibition appears to be mediated by a reduction in phosphorylation of p44/42 and p38 mitogen-activated protein kinase (MAPK). Though preliminary, our findings suggest the existence of a brain cholinergic pathway that regulates microglial activation through a7 nicotinic receptors. Negative regulation of microglia activation may also represent additional mechanism underlying nicotine's reported neuroprotective properties.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by deposition of ␤-amyloid (A␤) peptides as senile plaques in the brain. Recent studies suggest that green tea flavonoids may be used for the prevention and treatment of a variety of neurodegenerative diseases. Here, we report that (-)-epigallocatechin-3-gallate (EGCG), the main polyphenolic constituent of green tea, reduces A␤ generation in both murine neuron-like cells (N2a) transfected with the human "Swedish" mutant amyloid precursor protein (APP) and in primary neurons derived from Swedish mutant APP-overexpressing mice (Tg APP sw line 2576). In concert with these observations, we find that EGCG markedly promotes cleavage of the ␣-C-terminal fragment of APP and elevates the N-terminal APP cleavage product, soluble APP-␣. These cleavage events are associated with elevated ␣-secretase activity and enhanced hydrolysis of tumor necrosis factor ␣-converting enzyme, a primary candidate ␣-secretase. As a validation of these findings in vivo, we treated Tg APP sw transgenic mice overproducing A␤ with EGCG and found decreased A␤ levels and plaques associated with promotion of the nonamyloidogenic ␣-secretase proteolytic pathway. These data raise the possibility that EGCG dietary supplementation may provide effective prophylaxis for AD.

Bipolar disorder is a severe mental illness characterized by mood swings of elation and depression. Family, twin, and adoption studies suggest a complex genetic etiology that may involve multiple susceptibility genes and an environmental component. To identify chromosomal loci contributing to vulnerability, we have conducted a genome-wide scan on Ϸ396 individuals from 22 multiplex pedigrees by using 607 microsatellite markers. Multipoint nonparametric analysis detected the strongest evidence for linkage at 13q32 with a maximal logarithm of odds (lod) score of 3.5 (P ‫؍‬ 0.000028) under a phenotype model that included bipolar I, bipolar II with major depression, schizoaffective disorder, and recurrent unipolar disorder. Suggestive linkage was found on 1q31-q32 (lod ‫؍‬ 2.67; P ‫؍‬ 0.00022) and 18p11.2 (lod ‫؍‬ 2.32; P ‫؍‬ 0.00054). Recent reports have linked schizophrenia to 13q32 and 18p11.2. Our genome scan identified other interesting regions, 7q31 (lod ‫؍‬ 2.08; P ‫؍‬ 0.00099) and 22q11-q13 (lod ‫؍‬ 2.1; P ‫؍‬ 0.00094), and also confirmed reported linkages on 4p16, 12q23-q24, and 21q22. By comprehensive screening of the entire genome, we detected unreported loci for bipolar disorder, found support for proposed linkages, and gained evidence for the overlap of susceptibility regions for bipolar disorder and schizophrenia.

Long non-coding RNA (lncRNAs) play a critical role in the development of cancers. LncRNA metastasis-associated lung adenocarcinoma transcript 1(MALAT1) has recently been identified to be involved in tumorigenesis of several cancers such as lung cancer, bladder cancer and so on. Here, we found that MALAT1 exist a higher fold change (Tumor/Normal) in clear cell kidney carcinoma (KIRC) from The Cancer Genome Atlas (TCGA) Data Portal and a negative correlation with miR-200s family. We further demonstrated MALAT1 promote KIRC proliferation and metastasis through sponging miR-200s in vitro and in vivo. In addition, miR-200c can partly reverse the MALAT1′s stimulation on proliferation and metastasis in KIRC. In summary we unveil a branch of the MALAT1/miR-200s/ZEB2 pathway that regulates the progression of KIRC. The inhibition of MALAT1 expression may be a promising strategy for KIRC therapy.

A nuntb¢ r of transcription factors contain so.called zinc finger domains for the inlcr~ction with their cognate DNA sequence, It tins ~¢n shown that rclnOWd or the zinc io,~s complcxed in these zinc t~n~ers abrol~atcs DNA bindin~ and transcription activation, Therefore we wanted to te~ the hypothesis that the activity of tritnscriptton factors could b~ reguhtted by physolo~,ical chel.ttors of zinc, A pron~inent candid~tv,¢ rot such a chdutor is the Cys-rich protci='b thionein (apometallothionein) that is inducible by heavy metal Io=ids, and by oilier environm~nlal stimuli, Here we show with DNA binding, and in Vitro trtmscription ass;¢ys that thionein indeed can in.ctlvat¢ the zinc flnger.containin~ $pl in != reversible manner. By contrast, transcriptio, fitclor Oct-I, which binds DNA via a borneo.domain, i.~, a helix-turn-helix motif not involving zinc ions, is refntctory to thionein action, We propo~ that modulation ofintracellular thlonein concentration is used for the coordinated reguhttion of =l large subset of genes w!mSe tnm~ription depends on zinc finger proteins.

Recently, we have shown that green tea polyphenol (؊)-epigallocatechin-3-gallate (EGCG) exerts a beneficial role on reducing brain A␤ levels, resulting in mitigation of cerebral amyloidosis in a mouse model of Alzheimer disease. EGCG seems to accomplish this by modulating amyloid precursor protein (APP) processing, resulting in enhanced cleavage of the ␣-COOH-terminal fragment (␣-CTF) of APP and corresponding elevation of the NH 2 -terminal APP product, soluble APP-␣ (sAPP-␣). These beneficial effects were associated with increased ␣-secretase cleavage activity, but no significant alteration in ␤-or ␥-secretase activities. To gain insight into the molecular mechanism whereby EGCG modulates APP processing, we evaluated the involvement of three candidate ␣-secretase enzymes, a-disintegrin and metalloprotease ( Proteolytic processing of amyloid precursor protein (APP)4 to form amyloid-␤ (A␤) peptides are implicated in the pathogenesis and progression of Alzheimer disease (AD) (1-4). A␤ peptides from 40 -42 amino acids in length are constituents of senile plaques in AD brain and exhibit direct or indirect neurotoxic effects (5). Processing of APP is accomplished by enzymes known as secretases. Whereas non-amyloidogenic ␣-secretase cleavage produces the amino-terminal product named soluble APP␣ (sAPP-␣) and the carboxyl-terminal fragment (CTF) ␣-CTF (also known as C83), the action of amyloidogenic ␤-secretase on APP results in the amino-terminal product sAPP-␤ and the carboxyl-terminal product ␤-CTF (also known as C99). Subsequent ␥-secretase complex cleavage of ␤-CTF yields ␥-CTF (also known as C57), and releases A␤ (6 -10). Promotion of ␣-secretase processing leads to both a reduction in A␤ and an increase in sAPP-␣, a protein that exhibits neuroprotective properties (11)(12)(13)(14). A number of studies have sought to discern the molecular identity of ␣-secretase, with the hope of targeting such enzyme(s) to modulate A␤ production (15,16).A number of reports have implicated members of the a-disintegrin and metalloprotease (ADAM) family, a family of zinc metalloproteases including ADAM9, -10, and -17, as putative ␣-secretase candidates (15-17). Lammich and colleagues (18) first described the ability of ADAM10 to act as an ␣-secretase, whereas Buxbaum and co-workers (19) reported that ADAM17 contributes to ␣-secretase processing of APP. Others have demonstrated the ability of ADAM9 to promote ␣-secretase cleavage (20). However, Asai and colleagues (17) reported that ADAM9, -10, and -17 all have roles in the processing of APP to sAPP-␣ in vitro. In cerebrospinal fluid from AD patients, ADAM10 and corresponding sAPP/␣-CTFs are decreased (21,22). Moreover, ADAM10 is also decreased in AD and Down syndrome brains (23). A report by Lopez-Perez and colleagues (24) implicates ADAM10 as a contributor to constitutive sAPP-␣ production, whereas ADAM17 (also known as tumor necrosis factor-␣ converting enzyme, TACE) is implicated in a regulated mechanism of sAPP-␣ production (24). Recently, Postina and colleagues (25) showed th...

Neurogenesis continues throughout the lifetime in the hippocampus, while the rate declines with brain aging. It has been hypothesized that reduced neurogenesis may contribute to age-related cognitive impairment. Ginsenoside Rg1 is an active ingredient of Panax ginseng in traditional Chinese medicine, which exerts anti-oxidative and anti-aging effects. This study explores the neuroprotective effect of ginsenoside Rg1 on the hippocampus of the D-gal (D-galactose) induced aging rat model. Sub-acute aging was induced in male SD rats by subcutaneous injection of D-gal (120 mg/kg·d) for 42 days, and the rats were treated with ginsenoside Rg1 (20 mg/kg·d, intraperitoneally) or normal saline for 28 days after 14 days of D-gal injection. In another group, normal male SD rats were treated with ginsenoside Rg1 alone (20 mg/kg·d, intraperitoneally) for 28 days. It showed that administration of ginsenoside Rg1 significantly attenuated all the D-gal-induced changes in the hippocampus, including cognitive capacity, senescence-related markers and hippocampal neurogenesis, compared with the D-gal-treated rats. Further investigation showed that ginsenoside Rg1 protected NSCs/NPCs (neural stem cells/progenitor cells) shown by increased level of SOX-2 expression; reduced astrocytes activation shown by decrease level of Aeg-1 expression; increased the hippocampal cell proliferation; enhanced the activity of the antioxidant enzymes GSH-Px (glutathione peroxidase) and SOD (Superoxide Dismutase); decreased the levels of IL-1β, IL-6 and TNF-α, which are the proinflammatory cytokines; increased the telomere lengths and telomerase activity; and down-regulated the mRNA expression of cellular senescence associated genes p53, p21Cip1/Waf1 and p19Arf in the hippocampus of aged rats. Our data provides evidence that ginsenoside Rg1 can improve cognitive ability, protect NSCs/NPCs and promote neurogenesis by enhancing the antioxidant and anti-inflammatory capacity in the hippocampus.

Although considered an immunologically privileged site, the central nervous system (CNS) can display significant inflammatory responses, which may play a pathogenic role in a number of neurological diseases. Microglia appear to be particularly important for initiating and sustaining CNS inflammation. These cells exist in a quiescent form in the normal CNS, but acquire macrophage-like properties (including active phagocytosis, upregulation of proteins necessary for antigen presentation, and production of proinflammatory cytokines) after stimulation with inflammatory substances such as lipopolysaccharide (LPS). Recent studies have focused on elucidating the role of neurons in the regulation of microglial inflammatory responses. In the present study, we demonstrate, using neuron-microglial cocultures, that neurons are capable of inhibiting LPS-induced tumor necrosis factor-alpha (TNF-alpha) production by microglia. This inhibition appears to be dependent on secretion of substances at axon terminals, as treatment with the presynaptic calcium channel blocker omega-conotoxin abolishes this inhibitory effect. Moreover, we show that conditioned medium from neuronal cultures similarly inhibits microglial TNF-alpha production, which provides additional evidence that neurons secrete inhibitory substances. We previously demonstrated that the transmembrane protein-tyrosine phosphatase CD45 plays an important role in negatively regulating microglial activation. The recent characterization of CD22 as an endogenous ligand of this receptor led us to investigate whether neurons express this protein. Indeed, we were able to demonstrate CD22 mRNA and protein expression in cultured neurons and mouse brain, using reverse transcriptase-polymerase chain reaction and antibody-based techniques. Furthermore, we show that neurons secrete CD22, which functions as an inhibitor of microglial proinflammatory cytokine production.