Journal of Molecular Neuroscience (J MOL NEUROSCI)

Publications in this journal

• Article: Involvement of KATP/PI3K/AKT/Bcl-2 Pathway in Hydrogen Sulfide-induced Neuroprotection Against the Toxicity of 1-methy-4-phenylpyridinium Ion

  Xiao-Qing Tang, Yuan-Yuan Zhuang, Li-Li Fan, Heng-Rong Fang, Cheng-Fang Zhou, Ping Zhang, Bi Hu
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  ABSTRACT: We previously reported that hydrogen sulfide (H2S) produces protection in PC12 cells during 1-methy-4-phenylpyridinium ion (MPP+) challenge. The present study aims to clarify the mechanisms underlying the neuroprotective effects of H2S. We showed that both glybenclamide, an ATP-sensitive potassium (KATP) channel blocker, and LY294002, a specific PI3K–AKT pathway inhibitor, reversed the neuroprotective effect of NaHS (a H2S donor) against MPP+-induced cytotoxicity to PC12 cells and that NaHS up-regulated the activity of AKT in PC12 cells, which was abolished by blockade of KATP channels with glybenclamide. In addition, NaHS up-regulated the expression of Bcl-2 and blocked MPP+-induced down-regulation of Bcl-2, and this augmentation of Bcl-2 expression was prevented by both glybenclamide and LY294002. These data provided the evidence that the neuroprotective action of H2S against MPP+ toxicity to PC12 cells is via the KATP/PI3K/AKT/Bcl-2 pathway. We also demonstrated that NaHS attenuated the inhibitory effect of MPP+ ERK1/2 activation in PC12 cells, whereas U0126, a specific MEK inhibitor, did not reverse the neuroprotective effect of NaHS, which indicated that attenuating MPP+-triggered down-regulation of ERK1/2 activation is involved in the protection of H2S against MPP+ neurotoxicity, but ERK1/2 is not an essential effector mediating the neuroprotective effect of H2S. In conclusion, the present observations identify a crucial role of the KATP/PI3K/AKT/Bcl-2 pathway in H2S-exerted neuroprotection against the toxicity of MPP+. Findings from the present study will help shed light on the mechanisms of H2S-elicited neuroprotective effects on MPP+ toxicity. KeywordsHydrogen sulfide–1-Methy-4-phenylpyridinium ion–Neuroprotection–ATP-sensitive potassium channels–PI3K/AKT–Bcl-2
  Journal of Molecular Neuroscience 04/2012; 46(2):442-449.
• Article: Reversibility of Tau-Related Cognitive Defects in a Regulatable FTD Mouse Model

  Astrid Sydow, Ann Van der Jeugd, Fang Zheng, Tariq Ahmed, Detlef Balschun, Olga Petrova, Dagmar Drexler, Lepu Zhou, Gabriele Rune, Eckhard Mandelkow, Rudi D’Hooge, Christian Alzheimer, Eva-Maria Mandelkow
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  ABSTRACT: The accumulation of proteins such as Tau is a hallmark of several neurodegenerative diseases, e.g., frontotemporal dementia (FTD). So far, many mouse models of tauopathies have been generated by the use of mutated or truncated human Tau isoforms in order to enhance the amyloidogenic character of Tau and to mimic pathological processes similar to those in FTD patients. Our inducible mice express the repeat domain of human Tau (TauRD) carrying the FTDP-17 mutation ΔK280 in a “pro-aggregant” and an “anti-aggregant” version. Based on the enhanced tendency of Tau to aggregate, only the “pro-aggregant” TauRD mice develop Tau pathology (hyperphosphorylation, coassembly of human and mouse Tau, synaptic loss, and neuronal degeneration). We have now carried out behavioral and electrophysiological analyses showing that only the pro-aggregant TauRD mice have impaired learning/memory and a distinct loss of LTP. Remarkably, after suppressing the pro-aggregant human TauRD, memory and LTP recover, while neuronal loss persists. Aggregates persist as well but change their composition from mixed human/mouse to mouse Tau only. The rescue of cognition and synaptic plasticity is explained by a partial recovery of spine synapses in the hippocampus. These results indicate a tight relationship between the amyloidogenic character of Tau and brain malfunction, and suggest that the cognitive impairment is caused by toxic human TauRD species rather than by mouse Tau aggregates. KeywordsFrontotemporal dementia–Tau–Aggregation–Transgenic mouse models–Tauopathy
  Journal of Molecular Neuroscience 04/2012; 45(3):432-437.
• Article: Unraveling the Role of Metal Ions and Low Catalytic Activity of Cytochrome C Oxidase in Alzheimer’s Disease

  Trevor Alleyne, Neetu Mohan, Jerome Joseph, Andrew Adogwa
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  ABSTRACT: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by high levels of aluminum and certain other metal ions in the brain: The disease is also characterized by low activity of brain cytochrome c oxidase (COX) but whether the elevated metal ions and the low COX activity are linked is not known. Moreover, COX is known to exhibit two catalytic rates (V max) and two substrate binding constants (K m) but it is not known which of these is affected in AD. In this study, we employed the Klatzo AD rabbit model to evaluate the impact of elevated metal ions on brain COX activity. New Zealand white rabbits were injected intra-cerebrally with 1.4% solutions of either AlCl3, FeCl3, CaCl2, or MgCl2; and 10days, later the brain mitochondria were isolated. Polarographic assay revealed that compared to the controls, all four metals led to decreases in the V max of the enzyme’s low affinity site. The respective decreases were; 16%, 36%, 18%, and 30%. The results suggest a sequence of events in vivo in which oxygen radical damage to mitochondria and COX leads to low ATP production and excess heme establishing conditions thought to be ideal for neurodegeneration. KeywordsCytochrome oxidase–Metal ions–Alzheimer’s–Brain
  Journal of Molecular Neuroscience 04/2012; 43(3):284-289.
• Article: Behavioral Variant Frontotemporal Dementia with Corticobasal Degeneration Pathology: Phenotypic Comparison to bvFTD with Pick’s Disease

  Katherine P. Rankin, Mary Catherine Mayo, William W. Seeley, Suzee Lee, Gil Rabinovici, Maria Luisa Gorno-Tempini, Adam L. Boxer, Michael W. Weiner, John Q. Trojanowski, Stephen J. DeArmond, Bruce L. Miller
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  ABSTRACT: Patients with corticobasal degeneration (CBD) pathology present with diverse clinical syndromes also associated with other neuropathologies, including corticobasal syndrome, progressive nonfluent aphasia, and an Alzheimer’s-type dementia. Some present with behavioral variant frontotemporal dementia (bvFTD), though this subtype still requires more detailed clinical characterization. All patients with CBD pathology and clinical assessment were reviewed (N = 17) and selected if they initially met criteria for bvFTD [bvFTD(CBD), N = 5]. Available bvFTD patients with Pick’s [bvFTD(Pick’s), N = 5] were selected as controls. Patients were also compared to healthy older controls [N = 53] on neuropsychological and neuroimaging measures. At initial presentation, bvFTD(CBD) showed few neuropsychological or motor differences from bvFTD(Pick’s). Neuropsychiatrically, they were predominantly apathetic with less florid social disinhibition and eating disturbances, and were more anxious than bvFTD(Pick’s) patients. Voxel-based morphometry revealed similar patterns of predominantly frontal atrophy between bvFTD groups, though overall degree of atrophy was less severe in bvFTD(CBD), who also showed comparative preservation of the frontoinsular rim, with dorsal > ventral frontal atrophy, and sparing of temporal and parietal structures relative to bvFTD(Pick’s) patients. Despite a remarkable overlap between the two patient types, bvFTD patients with underlying CBD pathology show subtle clinical features that may distinguish them from patients with Pick’s disease neuropathology. KeywordsCorticobasal degeneration–Frontotemporal dementia–Behavior–Neuropsychiatry–Neuropsychology–Neuropathology
  Journal of Molecular Neuroscience 04/2012; 45(3):594-608.
• Article: Stem Cell Transplantation in Multiple Sclerosis: Sharing the Experience

  Tatyana Ionova
  Journal of Molecular Neuroscience 04/2012; 38(1):82-82.
• Article: BACE1 gene promoter is differentially regulated

  Debomoy K. Lahiri, Bryan Maloney, Yuan-Wen Ge
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  ABSTRACT: The amyloid-β (Aβ) peptide, the proteolytic fragment of Aβ precursor protein (APP), aggregates and forms neuritic plaques, a major hallmark of Alzheimer's disease (AD). The limiting step in generating the Aβ peptide from APP is cleavage by the β-secretase enzyme, BACE1. Regulation of the BACE1 gene is likely to play an important role in AD etiology and treatment. We therefore studied the activity of a 4.1-kb 5′-flanking region (−3765/+364, +1 being the transcription start site) of the BACE1 gene, both in 5′- and 3′-deletion series and through Northern blotting. We show that the BACE1 promoter has regulatory activity throughout the 4.1-kb length, both positive and negative, and that this activity can be quantitatively modeled according to promoter sequence length, with the specific model depending on the presence of negative regulatory elements as the 5′-most portion of the sequence. We also examined a previously identified 141-bp proximal fragment (+224/+364) of the BACE1 promoter and two constituent (91- and 50-bp) subfragments. We report that the 91-bp fragment (+224/+314) is the most likely seat of neuronal expression of the BACE1 gene and that it is the portion of the 141-bp fragment that accounts for observed DNA-protein interactions in brain extracts. The 50-bp fragment (+315/+364), which showed significant reporter gene activity from the empty vector, binds nuclear proteins in a cell type-specific manner and contains the AP2 site as shown by the electrophoretic mobility shift assay. Overall, the 141-bp fragment had no strong matches within GenBank, and the 91-bp fragment is predicted to have several potential stem-loop sites. Taken together, BACE1 gene promoter activity is differentially regulated, and the 91-bp fragment represents a novel promoter region for cell type-specific regulation. This fragment might be a useful target to regulate BACE1 expression leading to Aβ production and to understand the neuropathogenesis of AD.
  Journal of Molecular Neuroscience 04/2012; 28(2):193-210.
• Article: Molecular analysis of trkC in the cat visual cortex.

  F Forooghian, L Kojic, Q Gu, C A Wong, S S Prasad
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  ABSTRACT: trkC belongs to the trk family of neurotrophin receptors. Several isoforms of trkC have been cloned to date; a full-length catalytic form containing a tyrosine kinase (TK) domain, three full-length isoforms with amino-acid insertions (14, 25, and 39 amino acids) in the TK domain, and five noncatalytic truncated forms that completely lack the TK domain. These isoforms have been studied in several mammalian species, including the pig, rat, mouse, monkey, and human. In this article we report the cloning and sequencing of five trkC isoforms isolated from 30-d postnatal cat visual cortex. The first isoform corresponded to the previously reported full-length trkC transcript containing the 14 amino-acid insert. To search for the presence of other inserts, reverse transcription polymerase chain reaction (RT-PCR) was performed on 30-d postnatal cat visual cortex mRNA using primers that flank the insertion site in the TK domain. Both the isoform containing the 14 amino-acid insert and the isoform lacking any insertion were present in abundant amounts, whereas the other two insert containing isoforms (TK25 and TK39) were much less abundant. The fifth isoform discovered corresponds to the previously reported truncated transcript. Overall, there is a high degree of identity (89-98%) and homology (97-99%) between the cat trkC nucleotide and amino-acid sequences among all mammals. The extracellular juxtamembrane domain was found to be highly divergent among all mammals that have been studied to date. This divergent region also included a proline deletion in the cat trkC sequence. This is the first report of the cloning, sequencing, and RT-PCR analysis of trkC in cat visual cortex, a system extensively studied using anatomical and physiological approaches.
  Journal of Molecular Neuroscience 04/2012; 14(1-2):39-51.
• Article: Interaction Between Cav2.1α1 and CaMKII in Cav2.1α1 Mutant Mice, Rolling Nagoya

  Eiki Takahashi, Kimie Niimi, Chitoshi Itakura
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  ABSTRACT: It has been reported earlier that interactions between Cav2.1α1 and calcium/calmodulin-dependent protein kinase II (CaMKII) in the presynaptic fraction and between the NMDA receptor subunit NR2B and CaMKII in the postsynaptic density (PSD) fraction are important for neuronal function. Cav2.1α1, CaMKII, and NR2B are predominantly expressed in the hippocampus. To examine the above interactions and CaMKII activity in the hippocampal presynapse and PSD of Rolling Nagoya mice carrying a mutation in Cav2.1α1 subunit, we performed immunoprecipitation and Western blot analyses. In the presynapse, the interaction between Cav2.1α1 and CaMKII and the phosphorylation of CaMKII (at Thr286) and its substrate Synapsin I (at Ser603) were decreased in mutant mice compared to wild-type mice. In the PSD, a similar pattern was observed for the interaction between NR2B and CaMKII and the phosphorylation of CaMKII (at Thr286) and its substrate AMPA receptor subunit glutamate receptor 1 (at Ser831) between mutant and wild-type mice. Our data indicate that disruption of the interaction between Cav2.1α1 and CaMKII may down-regulate presynaptic CaMKII activity and that Rolling Nagoya mice would be a useful model for examining presynaptic function. Keywords Rolling Nagoya mice-Interaction between Cav2.1α1 and CaMKII-Presynaptic CaMKII activity-Immunoprecipitation-Western blot
  Journal of Molecular Neuroscience 04/2012; 41(2):223-229.
• Article: Acetylcholine release in rapid synapses

  Yves Dunant
  Journal of Molecular Neuroscience 04/2012; 30(1):209-213.
• Article: Poly(ADP-ribose) polymerase during reperfusion after transient forebrain ischemia

  Robert P. Strosznajder, Roman Gadamski, Grzegorz A. Czapski, Henryk Jesko, Joanna B. Strosznajder
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  ABSTRACT: The activation of poly(ADP-ribose) polymerase (PARP) in the reperfused brain after ischemia has been assumed but never has been directly presented. Our studies indicate a different dynamic of PARP activity alteration in hippocampus during reperfusion after 3 and 10 min of transient forebrain ischemia in gerbils. The phasic stimulation of PARP activity was observed during reperfusion 15 min, 120 min, and 4 d after 3 min of ischemia with subsequent lowering of its activity close to control value on the seventh day of reperfusion. After 10 min of ischemic insult, PARP activity significantly increased from the third to the seventh day of reperfusion. The protein level of PARP was not significantly changed during reperfusion after 3 and 10 min of ischemia, with one exception: On the third day after 10 min of ischemia, PARP protein level was 28% lower compared to control; however, no enhancement of 85-kDa protein immunoreactivity was observed. These data indicate the lack of PARP cleavage in hippocampus of gerbils subjected to ischemia-reperfusion injury. The inhibitor of PARP, 3-aminobenzamide (3-AB) in a dose of 30 mg/kg b.w. (body weight) injected intravenously directly after 3 min of ischemia protects >60% of neuronal cells against death in the CA1 layer of hippocampus but has no effect after 10 min of ischemic episode. 3-AB decreased forebrain edema significantly after 3 and 10 min of ischemia. Our data indicate that PARP inhibitor(s) might offer a potent therapeutic strategy for short global ischemia. The combination of PARP inhibitor with potent antioxidant might enhance its ameliorating effect.
  Journal of Molecular Neuroscience 04/2012; 20(1):61-71.
• Article: Domain-dependent modulation of PDGFRβ by ganglioside GM1

  Janet L. Oblinger, Cynthia L. Boardman, Allan J. Yates, Richard W. Burry
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  ABSTRACT: The regulation of receptor tyrosine kinases (RTKs) is important in several cellular events, including proliferation, differentiation, and apoptosis. Gangliosides are sialic acid-containing glycosphingolipids that can regulate RTK activity. The addition of ganglioside GM1 to the medium of Swiss 3T3 fibroblasts inhibits both platelet-derived growth factor (PDGF)-mediated tyrosine phosphorylation of PDGF receptor β (PDGFRβ) and receptor-mediated endocytosis. However, GM1 did not affect PDGF-mediated receptor phosphorylation, neuritogenesis, or endocytosis in PC12 cells stably transfected with the gene for PDGFRβ. The ability of GM1 to modulate PDGFRβ in 3T3 cells but not in transfected PC12 cells indicates a cell context-dependent response. We hypothesized that this inhibition of PDGFRβ by GM1 must map to one or more domains of the receptor. Thus, a chimeric receptor was created that possessed the extracellular and transmembrane domains of the nerve growth factor (NGF) receptor TrkA and the cytoplasmic domain of PDGFRβ (TTβ). In 3T3 cells transfected with the TTβ construct, GM1 did not inhibit NGF-induced tyrosine phosphorylation of the chimeric receptor or of Erk1/2 in this cell line. GM1 still inhibited PDGF-mediated tyrosine phosphorylation of endogenous PDGFRβ and of Erk1/2 in Swiss TTβ cells. Thus, the cytoplasmic domain of PDGFRβ is not required for GM1-dependent inhibition of PDGFRβ in 3T3 cells. This suggests that the inhibition of PDGFRβ by GM1 in Swiss 3T3 fibroblasts maps to either the extracellular and/or transmembrane domain of PDGFRβ.
  Journal of Molecular Neuroscience 04/2012; 20(2):103-113.
• Article: Neuroscience collaborations meeting report

  Illana Gozes
  Journal of Molecular Neuroscience 04/2012; 21(1):55-56.
• Article: Tetanus toxin modulates serotonin transport in rat-brain neuronal cultures

  Patricia Pelliccioni, Carles Gil, Abderrahim Najib, Elisabet Sarri, Fernando Picatoste, José Aguilera
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  ABSTRACT: As has been previously described, tetanus toxin (TeTx) and its HC fragment inhibit the sodium-dependent 5-hydroxytryptamine (5-HT) uptake in rat-brain synaptosomes, probably through a kinase mechanism affecting the 5-HT transporter. Now, the inhibition of 5-HT uptake in neurons in primary culture by TeTx in a dose-dependent manner is described in this work. This effect is also produced by the nontoxic C-terminal fragment of the TeTx heavy chain (Hc-fragment), indicating that 5-HT uptake inhibition is a consequence of the toxin binding to the plasmatic membrane and not to its catalytic activity. This conclusion is supported by the fact that the 5-HT accumulation was not inhibited by the light chain of TeTx or the toxoid, and was even potentiated by botulinum neurotoxin A. These results correlate with the activation of phosphoinositide-phospholipase C activity in the cultures used in this study, this activity only being enhanced by TeTx and by its Hc-fragment. On the other hand, the use of tyrosine phosphorylation modulators indicates that both Na3VO4 and basic fibroblast growth factor (bFGF) produce an enhancement of 5-HT uptake in this system, which is also sensitive to TeTx inhibition. On the other hand, genistein alone is able to reduce the 5-HT transport in cultured neurons, and this effect did not appear to be additive to that elicited by TeTx. This result suggests that TeTx and genistein may share some events in their respective mechanisms of action. Furthermore, the incubation at different concentrations of 12-0-tetradecanoylphorbol 13-acetate (TPA) confirms the involvement of protein kinase C (PKC) in 5-HT transport modulation in rat-brain neuronal primary cultures. In summary, we shall demonstrate in this work that TeTx induces, through its Hc fragment, an inhibition of both basal and stimulated serotonin uptakes in primary neuronal cultures, in parallel to the activation of phosphoinositide-phospholipase C activity and PKC activation.
  Journal of Molecular Neuroscience 04/2012; 17(3):303-310.
• Article: Fatty acid uptake and incorporation in brain

  Quentin R. Smith, Hiroshi Nagura
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  ABSTRACT: The contributions of individual components of blood to brain [14C]palmitate uptake and incorporation were studied with the in situ brain perfusion technique in the pentobarbital-anesthetized rat. With whole-blood perfusate, brain unacylated [14C]palmitate uptake was linear with time and extrapolated to zero at T=0 s of perfusion. Tracer accumulated in brain with a blood-to-brain transfer coefficient of 1.8 ± 0.1 × 10−4 mL/s/g (whole cerebral hemisphere). Incorporation into brain lipids was rapid such that ∼40% of tracer in brain at 45 s of perfusion was in cerebral phospholipids and neutral lipids. Similar rates of uptake were obtained during unacylated [14C]palmitate perfusion in whole rat plasma, serum, or artificial saline containing 2–3% albumin, suggesting that albumin has a key role in determining [14C]palmitate uptake in brain. The excellent match in brain uptake rates between whole blood and albumin-containing saline fluid suggests that the perfusion technique will be useful method for quantifying the individual contributions of blood constituents and albumin binding on brain [14C]palmitate uptake.
  Journal of Molecular Neuroscience 04/2012; 16(2):167-172.
• Article: Allosteric Modulator Desformylflustrabromine Relieves the Inhibition of α2β2 and α4β2 Nicotinic Acetylcholine Receptors by β-Amyloid1–42 Peptide

  Anshul Pandya, Jerrel L. Yakel
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  ABSTRACT: Nicotinic acetylcholine receptors (nAChRs) are pentameric transmembrane proteins that belong to the cys-loop ligand-gated ion channel family. These receptors are widely expressed in the brain and implicated in the pathophysiology of many neurological conditions, including Alzheimer’s disease (AD), where typical symptoms include the loss of cognitive function and dementia. The presence of extracellular neuritic plaques composed of β amyloid (Aβ1–42) peptide is a characteristic feature of AD. Desformylflustrabromine (dFBr) is a positive allosteric modulator (PAM) for α4β2 nAChRs since it increases peak ACh responses without inducing a response on its own. Previously, the effect of dFBr on the α2β2 nAChR subtype was not known. The action of dFBr was tested on α2β2 receptors expressed in Xenopus oocytes. It was found that dFBr is also a PAM for the α2β2 receptor. Next we tested whether dFBr had any effect on the previously known block of both the α4β2 and α2β2 receptors by Aβ1–42. We found that the functional blockade of ACh-induced currents in oocytes expressing α4β2 and α2β2 receptors by Aβ1–42 was prevented by dFBr. We conclude that dFBr is a positive allosteric modulator for both α4β2 and α2β2 subtypes of nAChRs and that it also relieves the blockade of these receptors by Aβ1–42. This study demonstrates that PAMs for the non-α7 nAChRs have the potential to develop into clinically applicable drugs for AD and other disorders. KeywordsAlzheimer’s disease (AD)–Beta amyloid (Aβ1–42)–Desformylflustrabromine (dFBr)–Electrophysiology–Nicotinic acetylcholine receptors (nAChRs)–Positive allosteric modulators (PAMs)
  Journal of Molecular Neuroscience 04/2012; 45(1):42-47.
• Article: Association of NAD(P)H:Quinone Oxidoreductase 1 Polymorphism and Alzheimer’s Disease in Chinese

  Jian-Tao Bian, Hua-Lu Zhao, Zhen-Xin Zhang, Xiu-Hua Bi, Jun-Wu Zhang
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  ABSTRACT: Several lines of evidence support a role of oxidative stress in the pathology of Alzheimer’s disease (AD). NAD(P)H:quinone oxidoreductase 1 (NQO1) catalyzes the two-electron reduction of quinones, preventing their participation in redox cycling and subsequent generation of reactive oxygen species. We examined association between the NQO1 C609T gene polymorphism and sporadic AD in a Chinese population comprising 311 AD patients and 330 controls. Our results showed a higher T-allele frequency in the AD cases compared with the controls. The difference was close to but did not reach statistically significant level [p = 0.059; odds ratio (OR) T versus C = 1.236; 95% confidence interval (95% CI), 0.992–1.540]. A significantly low C/C genotype frequency in the AD cases compared with the controls was detected (p = 0.025; OR C/C versus C/T + T/T = 0.674; 95% CI, 1.049–2.098) and APOE ε4 status analysis revealed significant difference in the APOE ε4 non-carriers (p = 0.036; OR = 0.633; 95% CI, 1.027–2.427). In the ≥65years samples, significantly low C/C frequency in the AD cases in comparison with the controls was observed in the APOE ε4 non-carriers (p = 0.045; OR = 0.595; 95% CI, 1.010–2.794). These results indicated that the C/C genotype had a possible protective effect against AD development, and the T allele might be a weak risk factor for late onset AD.
  Journal of Molecular Neuroscience 04/2012; 34(3):235-240.
• Article: Neuregulins rescue PC12-ErbB-4 cells from cell death induced by β-amyloid peptide

  Ayelet Di Segni, Ezra Shaharabani, Reuven Stein, Ronit Pinkas-Kramarski
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  ABSTRACT: Neuregulins (NRGs), which are highly expressed in the nervous system, bind and activate two receptor tyrosine kinases, ErbB-3 and ErbB-4. We previously showed that NRG mediates survival of PC12-ErbB-4 cells from apoptosis induced by serum deprivation, tumor necrosis factor-α treatment, or H2O2. These effects of NRGs are mediated by the phosphoinositide 3-kinase (PI3K) signaling pathway. In the present study, we show that NRG induces a significant protective effect from β-amyloid 25–35 (Aβ[25–35]) peptide-induced cell death. The PI3K signaling pathway might be involved in this effect of NRG as the downstream effector of PI3K, protein kinase B (PKB/AkT), is activated by NRG in the presence of Aβ, and PKB/AkT activation is inhibited by the PI3K inhibitor, LY294002. In addition, our results demonstrate that Aβ-induced cell death is reduced by expression of activated PI3K. These results suggest that PI3K-dependent pathways might regulate the toxic effect of Aβ. In addition, Aβ induced alteration in the levels of the proapoptotic protein Bax. Neuregulin (NRG) treatment however, induced elevation in the levels of the antiapoptotic protein BclxL. The NRG-mediated BclxL elevation is regulated by protein kinase C (PKC), as NRG failed to elevate BclxL in the presence of the PKC inhibitor, GF109203X. Moreover, activation of PKC by phorbol 12-myristate 13-acetate markedly attenuated cell death induced by Aβ and induced elevation in BclxL levels. The results suggest that NRG might affect cell viability using two signaling pathways: activation of PI3K/PKB/AkT pathway and activation of PKC, which results in increasing levels of the antiapoptotic protein BclxL.
  Journal of Molecular Neuroscience 04/2012; 26(1):57-70.