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• A seed for Alzheimer amyloid in the brain.
• Citation:
  Hayashi H, Kimura N, Yamaguchi H, Hasegawa K, Yokoseki T, Shibata M, Yamamoto N, Michikawa M, Yoshikawa Y, Terao K, Matsuzaki K, Lemere C, Selkoe D, Naiki H, Yanagisawa K
  

  A seed for Alzheimer amyloid in the brain.

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 2004 May 19;24(20):4894-902
  [PubMed] [Alzforum]
• Supporting:
  • The polymerization of soluble Aβ, which leads to plaque formation, is nucleated by “seeds” of oligomeric Aβ, but it remains unclear where seeds of polymerized Aβ originate or how they are formed.

    SHOW Details   Supporting(9)   Consistent(3) 

    Description: Since plaques contain at their core Aβ aggregates, it was assumed that aggregation of Aβ is the key event in plaque formation. Since Aβ undergoes spontaneous aggregation only at concentrations much higher than the ~10 nM physiological concentration, it was postulated that Aβ aggregation in AD is facilitated by disease-specific factors. A different view is offered by the seeded polymerization hypothesis of Harper and Lansbury. According to them, polymerization of extracellular, soluble Aβ requires a “seed” of aggregated Aβ that serves to nucleate further polymerization. It was proposed that the seed may contain a modified Aβ species that has high propensity to aggregate, such as the GM1 ganglioside-bound Aβ. An altered APP metabolism or transport, or inefficient clearance of Aβ could also cause abnormal local accumulation of Aβ, and somehow “force” its aggregation. The fact that “seeds” of Aβ are present in AD brains and can efficiently nucleate plaques was elegantly shown in studies where amyloidogenesis was induced in APP transgenic mice by intracerebral injection of extracts from AD brains. Still, questions such as: What is the seed? Where does it come from? How is it formed? are unanswered, and are addressed by our hypothesis.
    Experimental Approach: Mechanism - biochemistry and structural biology,   Mechanism - molecular and cell,  
    Pathogenic Narrative Tags: Pathogenic event
    Supporting Evidence
    

    • Harper J, Lansbury P
      Models of amyloid seeding in Alzheimer's disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins.
      Annual review of biochemistry. 1997;66:385-407
    • Zhang Q, Powers E, Nieva J, Huff M, Dendle M, Bieschke J, Glabe C, Eschenmoser A, Wentworth P, Lerner R, Kelly J
      Metabolite-initiated protein misfolding may trigger Alzheimer's disease.
      Proceedings of the National Academy of Sciences of the United States of America. 2004 Apr 6;101(14):4752-7
    • Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E, Neuenschwander A, Abramowski D, Frey P, Jaton A, Vigouret J, Paganetti P, Walsh D, Mathews P, Ghiso J, Staufenbiel M, Walker L, Jucker M
      Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host.
      Science (New York, N.Y.). 2006 Sep 22;313(5794):1781-4
    • Hayashi H, Kimura N, Yamaguchi H, Hasegawa K, Yokoseki T, Shibata M, Yamamoto N, Michikawa M, Yoshikawa Y, Terao K, Matsuzaki K, Lemere C, Selkoe D, Naiki H, Yanagisawa K
      A seed for Alzheimer amyloid in the brain.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2004 May 19;24(20):4894-902
    • Mizuno T, Nakata M, Naiki H, Michikawa M, Wang R, Haass C, Yanagisawa K
      Cholesterol-dependent generation of a seeding amyloid beta-protein in cell culture.
      The Journal of biological chemistry. 1999 May 21;274(21):15110-4
    • Lansbury P
      Structural neurology: are seeds at the root of neuronal degeneration?
      Neuron. 1997 Dec;19(6):1151-4
    • Kane M, Lipinski W, Callahan M, Bian F, Durham R, Schwarz R, Roher A, Walker L
      Evidence for seeding of beta -amyloid by intracerebral infusion of Alzheimer brain extracts in beta -amyloid precursor protein-transgenic mice.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2000 May 15;20(10):3606-11
    • Kamal A, Almenar-Queralt A, LeBlanc J, Roberts E, Goldstein L
      Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP.
      Nature. 2001 Dec 6;414(6864):643-8
    • Bieschke J, Zhang Q, Powers E, Lerner R, Kelly J
      Oxidative metabolites accelerate Alzheimer's amyloidogenesis by a two-step mechanism, eliminating the requirement for nucleation.
      Biochemistry. 2005 Apr 5;44(13):4977-83

    Consistent statements
    

    • Aβ deposition is promoted by increased concentration of Aβ or increased rate of seeding. Golde T 
    • Conversion of Aβ from a soluble form to fibrillar form occurs via “seeded” polymerization of Aβ40 and Aβ42. Holtzman D 
    • Amyloid increases through Aβ concentration-dependent seeded polymerization. Golde T 
• Created On: Tue, Nov 11 10:50:55 EST 2008
• Last Modified On: Tue Nov 11 10:50:55 EST 2008