title: Searching for an endogenous anti-Alzheimer molecule: identifying small molecules in the brain that slow Alzheimer disease progression by inhibition of ß-amyloid aggregation.
abstract: BACKGROUND
  Alzheimer disease is a neurodegenerative disorder that progresses with marked interindividual clinical variability. We postulate the existence of endogenous molecules within the human brain exerting an antiaggregant activity that will prevent/slow Alzheimer disease progression.
  
  
  METHODS
  We performed in silico studies to determine if the small endogenous molecules L-phosphoserine (L-PS) and 3-hydroxyanthranilic acid (3-HAA) could bind to the target region of ß-amyloid responsible for protein misfolding. In vitro assays measured the antiaggregation effect of these molecules at varying concentrations.
  
  
  RESULTS
  In silico studies demonstrated that L-PS and 3-HAA, both endogenous brain molecules, were capable of binding to the histidine(13)-histidine-glutamine-lysine(16) (HHQK) region of ß-amyloid involved in misfolding: these interactions were energetically favoured. The in vitro assays showed that both L-PS and 3-HAA were capable of inhibiting ß-amyloid aggregation in a dose-dependent manner, with 3-HAA being more potent than L-PS.
  
  
  CONCLUSIONS
  Studies were performed in silico and in vitro but not in vivo.
  
  
  CONCLUSIONS
  We successfully identified 2 endogenous brain molecules, L-PS and 3-HAA, that were capable of binding to the region of ß-amyloid that leads to protein misfolding and neurotoxicity. Both L-PS and 3-HAA were able to inhibit ß-amyloid aggregation in varying concentrations; levels of these compounds in the brain may impact their effectiveness in slowing/preventing ß-amyloid aggregation.
authors: Department of Chemistry, Dalhousie University, Halifax, NS, Canada.
authors: Autumn R
authors: AR
authors: Meek
authors: Gordon A
authors: GA
authors: Simms
authors: Donald F
authors: DF
authors: Weaver
mesh_terms: D015095:3-Hydroxyanthranilic Acid / Q000378:metabolism*; D000544:Alzheimer Disease / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D003198:Computer Simulation; D066298:In Vitro Techniques; D010768:Phosphoserine / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D016229:Amyloid beta-Peptides; D010768:Phosphoserine; D015095:3-Hydroxyanthranilic Acid
references: Anal Biochem. 2010 Oct 15;405(2):260-2
references: 20599655
references: Neurology. 1991 Apr;41(4):479-86
references: 2011243
references: Biochemistry. 1998 Aug 4;37(31):11064-77
references: 9693002
references: Biochemistry. 1994 Jun 28;33(25):7788-96
references: 7516706
references: Nucleic Acids Res. 2000 Jan 1;28(1):235-42
references: 10592235
references: J Neurochem. 2007 Jun;101(5):1172-84
references: 17286590
references: Eur J Biochem. 2002 Nov;269(22):5642-8
references: 12423364
references: J Biol Chem. 2006 Jan 27;281(4):2151-61
references: 16301322
references: Pharmacogenomics J. 2004;4(3):138-40
references: 15024381
references: Biochemistry. 2006 Apr 18;45(15):4727-35
references: 16605241
references: Neurobiol Aging. 2004 May-Jun;25(5):581-7
references: 15172733
references: Neurosci Lett. 2000 Jul 7;288(1):37-40
references: 10869810
references: Trends Biochem Sci. 2011 Jun;36(6):338-45
references: 21411326
references: J R Soc Interface. 2012 Jan 7;9(66):119-26
references: 21653567
references: Eur J Biochem. 1995 Oct 1;233(1):293-8
references: 7588758
references: J Neurol Sci. 2010 Mar 15;290(1-2):96-101
references: 19931870
references: Biochem Biophys Res Commun. 2008 Nov 7;376(1):56-9
references: 18755140
references: Chembiochem. 2006 Feb;7(2):257-67
references: 16444756
references: Redox Rep. 2010;15(4):161-8
references: 20663292
references: J Neurochem. 1991 Jun;56(6):1997-2003
references: 1673996
references: Psychoneuroendocrinology. 2007 Aug;32 Suppl 1:S62-70
references: 17659844
references: Neurobiol Aging. 2000 Nov-Dec;21(6):845-61
references: 11124429
references: Biophys Chem. 2010 Mar;147(1-2):81-6
references: 20060637
references: FEBS Lett. 2005 Feb 28;579(6):1338-42
references: 15733838
references: J Biol Chem. 1998 Nov 6;273(45):29719-26
references: 9792685