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• Author/Creator:Kaufman, Adam Craig.
  
• Title:Modulation of the PrPc Pathway Ameliorates A [Beta]o Induced Dysfunction [electronic resource].
  
• ISBN:9781339461540
  
• Physical Description:1 online resource (165 p.)
  
• Links:Online thesis
  

• Yale Holdings

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  • Location:Yale Internet Resource
    Information about Off Campus Access
    
    
  • Call Number: None
    
  • Status:No information available 
  • Notes: Online Resource
    

   
• Local Notes:Access is available to the Yale community.
  
• Notes:Source: Dissertation Abstracts International, Volume: 77-06(E), Section: B.
  Adviser: Stephen M. Strittmatter.
  
• Access and use:Access restricted by licensing agreement. This item is not available from ProQuest Dissertations & Theses.
• Summary:Alzheimer's disease (AD) is the most common form of dementia affecting millions worldwide. The primary histopathological features of AD are amyloid-beta (Abeta) plaques and neurofibrillary tangles. Abeta oligomers (Abetao) are believed to be essential mediators of the synaptotoxicity and cell death that are characteristic of this illness. Recently, it has been shown that the cellular Prion Protein (PrPc) acts as a high-affinity binding partner for Abetao. Herein the necessity is examined of PrPc and proteins downstream of this receptor, mGluR5 and Fyn, for memory loss, synaptic loss, biochemical changes, and microgliosis in AD mouse models.
  Specifically, it is shown that therapeutic removal of PrPc on an APP/PS 1 background leads to behavioral recovery, biochemical recovery, and potentially synaptic recovery. Currently no effective disease modifying agents exist for the treatment of AD. However in mice expressing familial AD transgenes, mGluR5 antagonism reverses deficits in learning, memory and synapse density. Cell death and spine loss are also reduced.
  The Src family kinase inhibitor oncology compound, AZD0530, is repurposed for AD. AZD0530 potently inhibits Fyn and prevents both Abetao-induced Fyn signaling and downstream activation of the AD risk gene product, Pyk2, and of NR2B Glu receptors in brain slices. After treatment, AZD0530 dosing of APP/PS1 transgenic mice fully rescues spatial memory deficits and synaptic depletion, without altering APP or Abeta metabolism. Thus, modulation of all three of these proteins dissociates Abetao accumulation from behavioral impairment in these AD mice, and thus opens up potential avenues for treatments in humans.
  
• In_:Dissertation Abstracts International 77-06B(E).
  
• Format:Book
• Thesis note:Thesis (Ph.D.)--Yale University, 2015.
  
• Also listed under:Yale University.