Self-Propagative Replication of Aβ Oligomers Suggests Potential Transmissibility in Alzheimer Disease
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{"title"=>"Self-propagative replication of Aβ oligomers suggests potential transmissibility in Alzheimer disease", "type"=>"journal", "authors"=>[{"first_name"=>"Amit", "last_name"=>"Kumar", "scopus_author_id"=>"55950017700"}, {"first_name"=>"Kayla M.", "last_name"=>"Pate", "scopus_author_id"=>"56410712100"}, {"first_name"=>"Melissa A.", "last_name"=>"Moss", "scopus_author_id"=>"35615169900"}, {"first_name"=>"Dexter N.", "last_name"=>"Dean", "scopus_author_id"=>"56410400100"}, {"first_name"=>"Vijayaraghavan", "last_name"=>"Rangachari", "scopus_author_id"=>"14042208600"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84909635625", "pui"=>"600373172", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "doi"=>"10.1371/journal.pone.0111492", "issn"=>"19326203", "scopus"=>"2-s2.0-84909635625", "pmid"=>"25365422"}, "id"=>"81ca6bb6-454c-3b41-b6c4-e61bb49203dc", "abstract"=>"The aggregation of amyloid-β (Aβ) peptide and its deposition in parts of the brain form the central processes in the etiology of Alzheimer disease (AD). The low-molecular weight oligomers of Aβ aggregates (2 to 30 mers) are known to be the primary neurotoxic agents whose mechanisms of cellular toxicity and synaptic dysfunction have received substantial attention in the recent years. However, how these toxic agents proliferate and induce widespread amyloid deposition throughout the brain, and what mechanism is involved in the amplification and propagation of toxic oligomer species, are far from clear. Emerging evidence based on transgenic mice models indicates a transmissible nature of Aβ aggregates and implicates a prion-like mechanism of oligomer propagation, which manifests as the dissemination and proliferation of Aβ toxicity. Despite accumulating evidence in support of a transmissible nature of Aβ aggregates, a clear, molecular-level understanding of this intriguing mechanism is lacking. Recently, we reported the characterization of unique replicating oligomers of Aβ42 (12-24 mers) in vitro called Large Fatty Acid-derived Oligomers (LFAOs) (Kumar et al., 2012, J. Biol. Chem). In the current report, we establish that LFAOs possess physiological activity by activating NF-κB in human neuroblastoma cells, and determine the experimental parameters that control the efficiency of LFAO replication by self-propagation. These findings constitute the first detailed report on monomer - oligomer lateral propagation reactions that may constitute potential mechanism governing transmissibility among Aβ oligomers. These data support the previous reports on transmissible mechanisms observed in transgenic animal models.", "link"=>"http://www.mendeley.com/research/selfpropagative-replication-a%CE%B2-oligomers-suggests-potential-transmissibility-alzheimer-disease", "reader_count"=>36, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>4, "Researcher"=>7, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>2, "Student > Master"=>3, "Other"=>1, "Student > Bachelor"=>4, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>4, "Researcher"=>7, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>2, "Student > Master"=>3, "Other"=>1, "Student > Bachelor"=>4, "Professor"=>2}, "reader_count_by_subject_area"=>{"Engineering"=>3, "Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>5, "Agricultural and Biological Sciences"=>13, "Medicine and Dentistry"=>5, "Neuroscience"=>2, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>4, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>3}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>5}, "Neuroscience"=>{"Neuroscience"=>2}, "Chemistry"=>{"Chemistry"=>4}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>13}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"United Kingdom"=>1, "France"=>1, "Germany"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1777307"], "description"=>"<p>(A) Silver stain of LFAOs and globulomers generated using previously established protocols. (B) Immunoblot showing the comparison of seeding efficiency of LFAOs and globulomers. Lane C represents Aβ42 control after 72 h. Lanes 1, 4, and 7 show 2% (molar ratio) LFAOs, 2 and 5% (molar ratio) globulomers seed alone, respectively. Lanes 2 and 3 show total and supernatant of LFAOs seeded sample after 72 h, while lanes 5, 6, 8, and 9 show total and supernatant of 2 and 5% globulomers seeded sample after 72 h, respectively.</p>", "links"=>[], "tags"=>["propagation", "nf", "LFAO", "oligomer", "mechanism", "β aggregates", "ad"], "article_id"=>1227469, "categories"=>["Biological Sciences"], "users"=>["Amit Kumar", "Kayla M. Pate", "Melissa A. Moss", "Dexter N. Dean", "Vijayaraghavan Rangachari"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0111492.g006", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Comparison_of_seeding_behavior_of_globulomers_and_LFAOs_/1227469", "title"=>"Comparison of seeding behavior of globulomers and LFAOs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-03 03:43:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/1777303"], "description"=>"<p>. (A) Data derived from the immunoblots show the increase in LFAO molecular weight with increase in temperature. <i>Inset</i>, immunoblot of LFAOs heated at the indicated temperatures; Lane 1 shows unheated LFAO sample (60 ng), while lanes 60, 80, 100, and 120°C show LFAOs heated-treated at these temperatures. Single arrow represents the center of unheated LFAOs molecular weight band. (B & C) DLS and CD analyses of the heat-treated LFAOs. D) Immunoblot comparing self-propagation of unheated LFAOs v/s those that were pre-treated with 72 h incubation at 80,100, and 120°C. Lanes 1, 3, 5, & 7 are the seeds alone (20 ng) for unheated, 80, 100, & 120°C-treated LFAOs (lanes 1, 3, 5 & 7, respectively). Lanes 2, 4, 6, and 8 represent 20 µM Aβ42 incubated with seeds of unheated, 80, 100, & 120°C-treated LFAOs, respectively after 72 h. E) Quantitative increase in LFAO amounts derived from seeded reactions and based on the normalization procedure used in Fig. 3. The symbols * and ** represent p<0.05 and p<0.01 based on ANOVA statistical analysis.</p>", "links"=>[], "tags"=>["propagation", "nf", "LFAO", "oligomer", "mechanism", "β aggregates", "ad"], "article_id"=>1227465, "categories"=>["Biological Sciences"], "users"=>["Amit Kumar", "Kayla M. Pate", "Melissa A. Moss", "Dexter N. Dean", "Vijayaraghavan Rangachari"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0111492.g004", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_temperature_on_LFAOs_and_their_self_propagation_/1227465", "title"=>"Effect of temperature on LFAOs and their self-propagation", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-03 03:43:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/1777311"], "description"=>"<p>LFAOs are kinetically-trapped, off-pathway intermediates due to which their half-lives could be considerably longer than the on-pathway oligomers (* indicates that the condition is hypothetical and not derived from the data presented in the manuscript). The second important trait of LFAOs is that they are conformationally distinct to undergo replication via fibril-free monomer – oligomer interactions as indicated.</p>", "links"=>[], "tags"=>["propagation", "nf", "LFAO", "oligomer", "mechanism", "β aggregates", "ad"], "article_id"=>1227473, "categories"=>["Biological Sciences"], "users"=>["Amit Kumar", "Kayla M. Pate", "Melissa A. Moss", "Dexter N. Dean", "Vijayaraghavan Rangachari"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0111492.g007", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Schematic_indicating_the_8216_aggregation_funnel_8217_and_self_propagative_replication_of_LFAOs_/1227473", "title"=>"Schematic indicating the ‘aggregation funnel’ and self-propagative replication of LFAOs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-03 03:43:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/1777275"], "description"=>"<p>(A) Immunoblot showing different amounts of SEC-fractionated LFAOs. Lanes 1–7 correspond to 4, 19, 40, 80, 120, 250, & 500 ng of LFAOs, respectively. LFAOs show two distinct band distributions, a lower band centered around ∼56–70 kDa (single arrow) and an upper band between ∼80 and 110 kDa (double arrow) (B) Dot blot analysis of Aβ42 monomer, LFAOs, and fibrils probed using monoclonal antibodies OC, Ab5, and Ab9. The amount of sample used for dot blot was ∼250 ng and was kept constant for all the samples. (C) Schematic of LFAOs self-propagation reported earlier (27).</p>", "links"=>[], "tags"=>["propagation", "nf", "LFAO", "oligomer", "mechanism", "β aggregates", "ad"], "article_id"=>1227439, "categories"=>["Biological Sciences"], "users"=>["Amit Kumar", "Kayla M. Pate", "Melissa A. Moss", "Dexter N. Dean", "Vijayaraghavan Rangachari"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0111492.g001", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_LFAO_characterization_/1227439", "title"=>"LFAO characterization.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-03 03:43:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/1777289"], "description"=>"<p>(A) SH-SY5Y cells were incubated in the absence (control, CONT) or presence of 0.5 µM Aβ monomer (MON), LFAOs (LFAO), or fibrils (FIB) for 30 min. Parallel treatment with TNF-α (TNF) served as a positive control for NF-κB activation. Immunofluorescence staining was performed using nuclear DAPI (blue) in conjunction with an anti-NF-κB antibody (red) that selectively binds to the activated form of NF-κB. (B) NF-κB activation was quantified using MATLAB functions of original z-stack confocal images, normalized for nuclear volume, and reported relative to control. Error bars indicate SEM, n = 3. The symbols * and ** represent p<0.05 and p<0.01, respectively, relative to the negative control.</p>", "links"=>[], "tags"=>["propagation", "nf", "LFAO", "oligomer", "mechanism", "β aggregates", "ad"], "article_id"=>1227453, "categories"=>["Biological Sciences"], "users"=>["Amit Kumar", "Kayla M. Pate", "Melissa A. Moss", "Dexter N. Dean", "Vijayaraghavan Rangachari"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0111492.g002", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_LFAOs_on_human_SH_SY5Y_neuroblastoma_cells_/1227453", "title"=>"Effect of LFAOs on human SH-SY5Y neuroblastoma cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-03 03:43:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/1777305"], "description"=>"<p>(A) Immunoblot of LFAO and R-LFAO seeded sample after 96 h. ‘C’ represents the control sample in the absence of seed, lanes 1 and 2 show parent LFAO seed alone and seeded reaction after 96 h, respectively, while lanes 3 and 4 show R-LFAO seed alone and seeded reaction after 96 h, respectively. Single and double arrows indicate the parent LFAO seeds ∼56–70 kDa and formation of R-LFAO ∼80–110 kDa bands after propagation, respectively. (B) Comparison of quantitative fold increase after seeding with parent and R-LFAO.</p>", "links"=>[], "tags"=>["propagation", "nf", "LFAO", "oligomer", "mechanism", "β aggregates", "ad"], "article_id"=>1227467, "categories"=>["Biological Sciences"], "users"=>["Amit Kumar", "Kayla M. Pate", "Melissa A. Moss", "Dexter N. Dean", "Vijayaraghavan Rangachari"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0111492.g005", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Comparison_of_propagation_efficiency_of_parent_LFAOs_and_R_LFAOs_/1227467", "title"=>"Comparison of propagation efficiency of parent LFAOs and R-LFAOs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-03 03:43:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/1777298"], "description"=>"<p>(A) Immunoblot of 30 µM Aβ42 seeded with 0.2, 2, or 20% (molar ratio) LFAO seeds after 212 h. Lane 1 is the control Aβ42 incubated in the absence of seeds after 212 h. Lanes 2, 3, and 4 are 0.2, 2, or 20% (molar ratio) LFAO seeds alone, respectively. The amounts loaded in lanes 2, 3, and 4 are 4, 40, and 406 ng, respectively. Lanes 5, 6, and 7 are aliquots of 0.2, 2, and 20%-seeded reactions after 212 h, respectively. (B, C & D) Corresponding SEC chromatograms for the seeded reactions after 212 h. Solid lines and dashed lines correspond to seeded reactions and seed alone, respectively. (E) Quantitative increase of LFAO self-propagation for different seed amounts and at different time points. The data were obtained by normalizing the SEC chromatogram for the seeded reactions against the corresponding chromatograms of the seeds alone. The symbols •, *, **, and *** represent >90, >95, >99 and >99.9% confidence based on ANOVA statistical analysis.</p>", "links"=>[], "tags"=>["propagation", "nf", "LFAO", "oligomer", "mechanism", "β aggregates", "ad"], "article_id"=>1227460, "categories"=>["Biological Sciences"], "users"=>["Amit Kumar", "Kayla M. Pate", "Melissa A. Moss", "Dexter N. Dean", "Vijayaraghavan Rangachari"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0111492.g003", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Determination_of_LFAOs_seeding_efficiency_/1227460", "title"=>"Determination of LFAOs seeding efficiency.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-11-03 03:43:14"}

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