http://www.molecularneurodegeneration.com The latest research articles published by Molecular Neurodegeneration 2012-05-15T00:00:00Z Background: Cerebral ischemia has been shown to induce activation of matrix metalloproteinases (MMPs),particularly MMP-9, which is associated with impairment of the neurovasculature, resultingin blood-brain barrier breakdown, hemorrhage and neurodegeneration. We previouslyreported that the thiirane inhibitor SB-3CT, which is selective for gelatinases (MMP-2 and9), could antagonize neuronal apoptosis after transient focal cerebral ischemia. Results: Here, we used a fibrin-rich clot to occlude the middle cerebral artery (MCA) and assessed theeffects of SB-3CT on the neurovasculature. Results show that neurobehavioral deficits andinfarct volumes induced by embolic ischemia are comparable to those induced by thefilament-occluded transient MCA model. Confocal microscopy indicated embolus-blockedbrain microvasculature and neuronal cell death. Post-ischemic SB-3CT treatment attenuatedinfarct volume, ameliorated neurobehavioral outcomes, and antagonized the increases inlevels of proform and activated MMP-9. Embolic ischemia caused degradation of theneurovascular matrix component laminin and tight-junction protein ZO-1, contraction ofpericytes, and loss of lectin-positive brain microvessels. Despite the presence of the embolus,SB-3CT mitigated these outcomes and reduced hemorrhagic volumes. Interestingly, SB-3CTtreatment for seven days protected against neuronal laminin degradation and protectedneurons from ischemic cell death. Conclusion: These results demonstrate considerable promise for the thiirane class of selective gelatinaseinhibitors as potential therapeutic agents in stroke therapy. http://www.molecularneurodegeneration.com/content/7/1/21 Jiankun Cui Shanyan Chen Chunyang Zhang Fanjun Meng Wei Wu Rong Hu Or Hadass Tareq Lehmidi Gregory Blair Mijoon Lee Mayland Chang Shahriar Mobashery Grace Sun Zezong Gu Molecular Neurodegeneration 2012, null:21 2012-05-15T00:00:00Z doi:10.1186/1750-1326-7-21 /content/figures/1750-1326-7-21-toc.gif Molecular Neurodegeneration 1750-1326 ${item.volume} 21 2012-05-15T00:00:00Z PDF Background: Despite enormous progress in elucidating the biophysics of aggregation, no cause-and-effectrelationship between protein aggregation and neurodegenerative disease has beenunequivocally established. Here, we derived several risk-based stochastic kinetic models thatassess genotype/phenotype correlations in patients with Huntington's disease (HD) caused bythe expansion of a CAG repeat. Fascinating disease-specific aspects of HD include thepolyglutamine (polyQ)-length dependence of both age at symptoms onset and the propensityof the expanded polyQ protein to aggregate. In vitro, aggregation of polyQ peptides follows asimple nucleated growth polymerization pathway. Our models that reflect polyQ aggregationkinetics in a nucleated growth polymerization divided aggregate process into the lengthdependentnucleation and the nucleation-dependent elongation. In contrast to the repeatlengthdependent variability of age at onset, recent studies have shown that the extent ofexpansion has only a subtle effect on the rate of disease progression, suggesting possibledifferences in the mechanisms underlying the neurodegenerative process. Results: Using polyQ-length as an index, these procedures enabled us for the first time to establish aquantitative connection between aggregation kinetics and disease process, including onsetand the rate of progression. Although the complexity of disease process in HD, the timecourse of striatal neurodegeneration can be precisely predicted by the mathematical model inwhich neurodegeneration occurs by different mechanisms for the initiation and progression ofdisease processes. Nucleation is sufficient to initiate neuronal loss as a series of randomevents in time. The stochastic appearance of nucleation in a cell population acts as theconstant risk of neuronal cell damage over time, while elongation reduces the risk bynucleation in proportion to the increased extent of the aggregates during disease progression. Conclusions: Our findings suggest that nucleation is a critical step in gaining toxic effects to the cell, andprovide a new insight into the relationship between polyQ aggregation and neurodegenerativeprocess in HD. http://www.molecularneurodegeneration.com/content/7/1/20 Keizo Sugaya Shiro Matsubara Molecular Neurodegeneration 2012, null:20 2012-05-14T00:00:00Z doi:10.1186/1750-1326-7-20 /content/figures/1750-1326-7-20-toc.gif Molecular Neurodegeneration 1750-1326 ${item.volume} 20 2012-05-14T00:00:00Z PDF Background: A mutation in the BRI2/ITM2b gene causes familial Danish dementia (FDD). BRI2 is aninhibitor of amyloid-beta precursor protein (APP) processing, which is genetically linked toAlzheimer's disease (AD) pathogenesis. The FDD mutation leads to a loss of BRI2 proteinand to increased APP processing. APP haplodeficiency and inhibition of APP cleavage by beta-secretase rescue synaptic/memory deficits of a genetically congruous mouse model of FDD(FDDKI). beta-cleavage of APP yields the beta-carboxyl-terminal (beta-CTF) and the amino-terminalsolubleAPPbeta (sAPPbeta) fragments. gamma-secretase processing of beta-CTF generates Abeta, which isconsidered the main cause of AD. However, inhibiting Abeta production did not rescue thedeficits of FDDK mice, suggesting that sAPPbeta/beta-CTF, and not Abeta, are the toxic speciescausing memory loss. Results: Here, we have further analyzed the effect of gamma-secretase inhibition. We show that treatmentwith a gamma-secretase inhibitor (GSI) results in a worsening of the memory deficits of FDDKImice. This deleterious effect on memory correlates with increased levels of the beta/alpha-CTFsAPP fragments in synaptic fractions isolated from hippocampus of FDDKI mice, which isconsistent with inhibition of gamma-secretase activity. Conclusion: This harmful effect of the GSI is in sharp contrast with a pathogenic role for Abeta, and suggeststhat the worsening of memory deficits may be due to accumulation of synaptic-toxic beta/alpha-CTFs caused by GSI treatment. However, gamma-secretase cleaves more than 40 proteins; thus, thenoxious effect of GSI on memory may dependent on inhibition of cleavage of one or more ofthese other gamma-secretase substrates. These two possibilities do not need to be mutuallyexclusive. Our results are consistent with the outcome of a clinical trial with the GSISemagacestat, which caused a worsening of cognition, and advise against targeting gamma-secretase in the therapy of AD. Overall, the data also indicate that FDDKI is a valuable mousemodel to study AD pathogenesis and predict the clinical outcome of therapeutic agents forAD. http://www.molecularneurodegeneration.com/content/7/1/19 Robert Tamayev Luciano D'Adamio Molecular Neurodegeneration 2012, null:19 2012-04-26T00:00:00Z doi:10.1186/1750-1326-7-19 /content/figures/1750-1326-7-19-toc.gif Molecular Neurodegeneration 1750-1326 ${item.volume} 19 2012-04-26T00:00:00Z PDF Background: Prion disease transmission and pathogenesis are linked to misfolded, typically protease resistant (PrPres) conformers of the normal cellular prion protein (PrPC), with the former posited to be the principal constituent of the infectious 'prion'. Unexplained discrepancies observed between detectable PrPres and infectivity levels exemplify the complexity in deciphering the exact biophysical nature of prions and those host cell factors, if any, which contribute to transmission efficiency. In order to improve our understanding of these important issues, this study utilized a bioassay validated cell culture model of prion infection to investigate discordance between PrPres levels and infectivity titres at a subcellular resolution.FindingsSubcellular fractions enriched in lipid rafts or endoplasmic reticulum/mitochondrial marker proteins were equally highly efficient at prion transmission, despite lipid raft fractions containing up to eight times the levels of detectable PrPres. Brain homogenate infectivity was not differentially enhanced by subcellular fraction-specific co-factors, and proteinase K pre-treatment of selected fractions modestly, but equally reduced infectivity. Only lipid raft associated infectivity was enhanced by sonication. Conclusions: This study authenticates a subcellular disparity in PrPres and infectivity levels, and eliminates simultaneous divergence of prion strains as the explanation for this phenomenon. On balance, the results align best with the concept that transmission efficiency is influenced more by intrinsic characteristics of the infectious prion, rather than cellular microenvironment conditions or absolute PrPres levels. http://www.molecularneurodegeneration.com/content/7/1/18 Victoria Lewis Cathryn Haigh Colin Masters Andrew Hill Victoria Lawson Steven Collins Molecular Neurodegeneration 2012, null:18 2012-04-26T00:00:00Z doi:10.1186/1750-1326-7-18 /content/figures/1750-1326-7-18-toc.gif Molecular Neurodegeneration 1750-1326 ${item.volume} 18 2012-04-26T00:00:00Z XML Background: A considerable proportion of all newly generated cells in the hippocampus will die beforebecoming fully differentiated, both under normal and pathological circumstances. Thecaspase-independent apoptosis-inducing factor (AIF) has not been investigated previously inthis context. Results: Postnatal day 8 (P8) harlequin (Hq) mutant mice, expressing lower levels of AIF, and wildtype littermates were injected with BrdU once daily for two days to label newborn cells. OnP10 mice were subjected to hypoxia-ischemia (HI) and their brains were analyzed 4 h, 24 hor 4 weeks later. Overall tissue loss was 63.5% lower in Hq mice 4 weeks after HI. Shorttermsurvival (4 h and 24 h) of labeled cells in the subgranular zone was neither affected byAIF downregulation, nor by HI. Long-term (4 weeks) survival of undifferentiated, BLBPpositivestem cells was reduced by half after HI, but this was not changed by AIFdownregulation. Neurogenesis, however, as judged by BrdU/NeuN double labeling, wasreduced by half after HI in wild type mice but preserved in Hq mice, indicating that primarilyneural progenitors and neurons were protected. A wave of cell death started early after HI inthe innermost layers of the granule cell layer (GCL) and moved outward, such that 24 h afterHI dying cells could be detected in the entire GCL. Conclusions: These findings demonstrate that AIF downregulation provides not only long-term overallneuroprotection after HI, but also protects neural progenitor cells, thereby rescuinghippocampal neurogenesis. http://www.molecularneurodegeneration.com/content/7/1/17 Yanyan Sun Yu Zhang Xiaoyang Wang Klas Blomgren Changlian Zhu Molecular Neurodegeneration 2012, null:17 2012-04-25T00:00:00Z doi:10.1186/1750-1326-7-17 /content/figures/1750-1326-7-17-toc.gif Molecular Neurodegeneration 1750-1326 ${item.volume} 17 2012-04-25T00:00:00Z PDF Background: Alcadeinalpha (Alcalpha) is a neuronal membrane protein that colocalizes with the Alzheimer'samyloid-beta precursor protein (APP). Successive cleavage of APP by beta- and gamma-secretasesgenerates the aggregatable amyloid-beta peptide (Abeta), while cleavage of APP or Alcalpha by alpha- andgamma-secretases generates non-aggregatable p3 or p3-Alcalpha peptides. Abeta and p3-Alcalpha can berecovered from human cerebrospinal fluid (CSF). We have previously reported alternativeprocessing of APP and Alcalpha in the CSF of some patients with sporadic mild cognitiveimpairment (MCI) and AD (SAD). Results: Using the sandwich enzyme-linked immunosorbent assay (ELISA) system that detects totalp3-Alcalpha, we determined levels of total p3-Alcalpha in CSF from subjects in one of four diagnosticcategories (elderly controls, MCI, SAD, or other neurological disease) derived from threeindependent cohorts. Levels of Abeta40 correlated with levels of total p3-Alca in all cohorts. Conclusions: We confirm that Abeta40 is the most abundant Abeta species, and we propose a model in whichCSF p3-Alca can serve as a either (1) a nonaggregatable surrogate marker for gamma-secretaseactivity; (2) as a marker for clearance of transmembrane domain peptides derived fromintegral protein catabolism; or (3) both. We propose the specification of an MCI/SADendophenotype characterized by co-elevation of levels of both CSF p3-Alcalpha and Abeta40, andwe propose that subjects in this category might be especially responsive to therapeutics aimedat modulation of gamma-secretase function and/or transmembrane domain peptide clearance. Thesepeptides may also be used to monitor the efficacy of therapeutics that target these steps in Abetametabolism. http://www.molecularneurodegeneration.com/content/7/1/16 Saori Hata Miyako Taniguchi Yi Piao Takeshi Ikeuchi Anne Fagan David Holtzman Randall Bateman Hamid Sohrabi Ralph Martins Sam Gandy Katsuya Urakami Toshiharu Suzuki Molecular Neurodegeneration 2012, null:16 2012-04-25T00:00:00Z doi:10.1186/1750-1326-7-16 /content/figures/1750-1326-7-16-toc.gif Molecular Neurodegeneration 1750-1326 ${item.volume} 16 2012-04-25T00:00:00Z PDF Background: Leucine-rich repeat kinase 2 (LRRK2) is the gene responsible for autosomal-dominantParkinson's disease (PD), PARK8, but the mechanism by which LRRK2 mutations causeneuronal dysfunction remains unknown. In the present study, we investigated for the firsttime a transgenic (TG) mouse strain expressing human LRRK2 with an I2020T mutation inthe kinase domain, which had been detected in the patients of the original PARK8 family. Results: The TG mouse expressed I2020T LRRK2 in dopaminergic (DA) neurons of the substantianigra, ventral tegmental area, and olfactory bulb. In both the beam test and rotarod test, theTG mice exhibited impaired locomotive ability in comparison with their non-transgenic(NTG) littermates. Although there was no obvious loss of DA neurons in either the substantianigra or striatum, the TG brain showed several neurological abnormalities such as a reducedstriatal dopamine content, fragmentation of the Golgi apparatus in DA neurons, and anincreased degree of microtubule polymerization. Furthermore, the tyrosine hydroxylasepositiveprimary neurons derived from the TG mouse showed an increased frequency ofapoptosis and had neurites with fewer branches and decreased outgrowth in comparison withthose derived from the NTG controls. Conclusions: The I2020T LRRK2 TG mouse exhibited impaired locomotive ability accompanied byseveral dopaminergic neuron abnormalities. The TG mouse should provide valuable clues tothe etiology of PD caused by the LRRK2 mutation. http://www.molecularneurodegeneration.com/content/7/1/15 Tatsunori Maekawa Sayuri Mori Yui Sasaki Takashi Miyajima Sadahiro Azuma Etsuro Ohta Fumiya Obata Molecular Neurodegeneration 2012, null:15 2012-04-25T00:00:00Z doi:10.1186/1750-1326-7-15 /content/figures/1750-1326-7-15-toc.gif Molecular Neurodegeneration 1750-1326 ${item.volume} 15 2012-04-25T00:00:00Z PDF Background: Abnormal proteostasis due to alterations in protein turnover has been postulated to play acentral role in several neurodegenerative diseases. Therefore, the development of techniquesto quantify protein turnover in the brain is critical for understanding the pathogenicmechanisms of these diseases. We have developed a bolus stable isotope-labeling kinetics(SILK) technique coupled with multiple reaction monitoring mass spectrometry to measurethe clearance of proteins in the mouse brain. Results: Cohorts of mice were pulse labeled with 13 C6-leucine and the brains were isolated after predeterminedtime points. The extent of label incorporation was measured over time using massspectrometry to measure the ratio of labeled to unlabeled apolipoprotein E (apoE) andamyloid beta (Abeta). The fractional clearance rate (FCR) was then calculated by analyzing thetime course of disappearance for the labeled protein species. To validate the technique, apoEclearance was measured in mice that overexpress the low-density lipoprotein receptor(LDLR). The FCR in these mice was 2.7-fold faster than wild-type mice. To demonstrate thepotential of this technique for understanding the pathogenesis of neurodegenerative disease,we applied our SILK technique to determine the effect of ATP binding cassette A1 (ABCA1)on both apoE and Abeta clearance. ABCA1 had previously been shown to regulate both theamount of apoE in the brain, along with the extent of Abeta deposition, and represents apotential molecular target for lowering brain amyloid levels in AD patients. The FCR of apoEwas increased by 1.9- and 1.5-fold in mice that either lacked or overexpressed ABCA1,respectively. However, ABCA1 had no effect on the FCR of Abeta, suggesting that ABCA1does not regulate Abeta metabolism in the brain. Conclusions: Our SILK strategy represents a straightforward, cost-effective, and efficient method tomeasure the clearance of brain proteins in the mouse brain. We expect that this technique willbe applicable to the study of protein dynamics in the pathogenesis of severalneurodegenerative diseases, and could aid in the evaluation of novel therapeutic agents. http://www.molecularneurodegeneration.com/content/7/1/14 Jacob Basak Jungsu Kim Yuriy Pyatkivskyy Kristin Wildsmith Hong Jiang Maia Parsadanian Bruce Patterson Randall Bateman David Holtzman Molecular Neurodegeneration 2012, null:14 2012-04-18T00:00:00Z doi:10.1186/1750-1326-7-14 /content/figures/1750-1326-7-14-toc.gif Molecular Neurodegeneration 1750-1326 ${item.volume} 14 2012-04-18T00:00:00Z PDF Background: Glutathione S-transferase omega-1 and 2 genes (GSTO1, GSTO2), residing within an Alzheimer and Parkinson disease (AD and PD) linkage region, have diverse functions including mitigation of oxidative stress and may underlie the pathophysiology of both diseases. GSTO polymorphisms were previously reported to associate with risk and age-at-onset of these diseases, although inconsistent follow-up study designs make interpretation of results difficult. We assessed two previously reported SNPs, GSTO1 rs4925 and GSTO2 rs156697, in AD (3,493 ADs vs. 4,617 controls) and PD (678 PDs vs. 712 controls) for association with disease risk (case-controls), age-at-diagnosis (cases) and brain gene expression levels (autopsied subjects). Results: We found that rs156697 minor allele associates with significantly increased risk (odds ratio = 1.14, p = 0.038) in the older ADs with age-at-diagnosis > 80 years. The minor allele of GSTO1 rs4925 associates with decreased risk in familial PD (odds ratio = 0.78, p = 0.034). There was no other association with disease risk or age-at-diagnosis. The minor alleles of both GSTO SNPs associate with lower brain levels of GSTO2 (p = 4.7 x 10-11-1.9 x 10-27), but not GSTO1. Pathway analysis of significant genes in our brain expression GWAS, identified significant enrichment for glutathione metabolism genes (p = 0.003). Conclusion: These results suggest that GSTO locus variants may lower brain GSTO2 levels and consequently confer AD risk in older age. Other glutathione metabolism genes should be assessed for their effects on AD and other chronic, neurologic diseases. http://www.molecularneurodegeneration.com/content/7/1/13 Mariet Allen Fanggeng Zou High Seng Chai Curtis Younkin Richard Miles Asha Nair Julia Crook V Shane Pankratz Minerva Carrasquillo Christopher Rowley Thuy Nguyen Li Ma Kimberly Malphrus Gina Bisceglio Alexandra Ortolaza Ryan Palusak Sumit Middha Sooraj Maharjan Constantin Georgescu Debra Schultz Fariborz Rakhshan Christopher Kolbert Jin Jen Sigrid Sando Jan Aasly Maria Barcikowska Ryan Uitti Zbigniew Wszolek Owen Ross Ronald Petersen Neill Graff-Radford Dennis Dickson Steven Younkin Nilufer Ertekin-Taner Molecular Neurodegeneration 2012, null:13 2012-04-11T00:00:00Z doi:10.1186/1750-1326-7-13 /content/figures/1750-1326-7-13-toc.gif Molecular Neurodegeneration 1750-1326 ${item.volume} 13 2012-04-11T00:00:00Z PDF BackgoundNo disease modifying treatment currently exists for Huntington's disease (HD), a fatal neurodegenerative disorder characterized by the formation of amyloid-like aggregates of the mutated huntingtin protein. Curcumin is a naturally occurring polyphenolic compound with Congo red-like amyloid binding properties and the ability to cross the blood brain barrier. CAG140 mice, a knock-in (KI) mouse model of HD, display abnormal aggregates of mutant huntingtin and striatal transcriptional deficits, as well as early motor, cognitive and affective abnormalities, many months prior to exhibiting spontaneous gait deficits, decreased striatal volume, and neuronal loss. We have examined the ability of life-long dietary curcumin to improve the early pathological phenotype of CAG140 mice. Results: KI mice fed a curcumin-containing diet since conception showed decreased huntingtin aggregates and increased striatal DARPP-32 and D1 receptor mRNAs, as well as an amelioration of rearing deficits. However, similar to other antioxidants, curcumin impaired rotarod behavior in both WT and KI mice and climbing in WT mice. These behavioral effects were also noted in WT C57Bl/6 J mice exposed to the same curcumin regime as adults. However, neither locomotor function, behavioral despair, muscle strength or food utilization were affected by curcumin in this latter study. The clinical significance of curcumin's impairment of motor performance in mice remains unclear because curcumin has an excellent blood chemistry and adverse event safety profile, even in the elderly and in patients with Alzheimer's disease. Conclusion: Together with this clinical experience, the improvement in several transgene-dependent parameters by curcumin in our study supports a net beneficial effect of dietary curcumin in HD. http://www.molecularneurodegeneration.com/content/7/1/12 Miriam Hickey Chunni Zhu Vera Medvedeva Renata Lerner Stefano Patassini Nicholas Franich Panchanan Maiti Sally Frautschy Scott Zeitlin Michael Levine Marie-Francoise Chesselet Molecular Neurodegeneration 2012, null:12 2012-04-04T00:00:00Z doi:10.1186/1750-1326-7-12 /content/figures/1750-1326-7-12-toc.gif Molecular Neurodegeneration 1750-1326 ${item.volume} 12 2012-04-04T00:00:00Z XML