From: drarwingnuttephd@gmail.com   
      
   Nicotinamide Restores Cognition in Alzheimer's Disease Transgenic Mice via a   
   Mechanism Involving Sirtuin Inhibition and Selective Reduction of   
   Thr231-Phosphotau   
   Kim N. Green1, Joan S. Steffan2, Hilda Martinez-Coria1, Xuemin Sun3, Steven S.   
   Schreiber3,5, Leslie Michels Thompson1,2,4, and Frank M. LaFerla1   
   +Show Affiliations   
   The Journal of Neuroscience, 5 November 2008, 28(45): 11500-11510; doi:   
   10.1523/JNEUROSCI.3203-08.2008   
      
   Abstract   
      
   Memory loss is the signature feature of Alzheimer's disease, and therapies   
   that prevent or delay its onset are urgently needed. Effective preventive   
   strategies likely offer the greatest and most widespread benefits. Histone   
   deacetylase (HDAC) inhibitors    
   increase histone acetylation and enhance memory and synaptic plasticity. We   
   evaluated the efficacy of nicotinamide, a competitive inhibitor of the   
   sirtuins or class III NAD+-dependent HDACs in 3xTg-AD mice, and found that it   
   restored cognitive deficits    
   associated with pathology. Nicotinamide selectively reduces a specific   
   phospho-species of tau (Thr231) that is associated with microtubule   
   depolymerization, in a manner similar to inhibition of SirT1. Nicotinamide   
   also dramatically increased acetylated α   
   -tubulin, a primary substrate of SirT2, and MAP2c, both of which are linked to   
   increased microtubule stability. Reduced phosphoThr231-tau was related to a   
   reduction of monoubiquitin-conjugated tau, suggesting that this    
   osttranslationally modified form    
   of tau may be rapidly degraded. Overexpression of a Thr231-phospho-mimic tau   
   in vitro increased clearance and decreased accumulation of tau compared with   
   wild-type tau. These preclinical findings suggest that oral nicotinamide may   
   represent a safe    
   treatment for AD and other tauopathies, and that phosphorylation of tau at   
   Thr231 may regulate tau stability.   
      
      
   http://www.jneurosci.org/content/28/45/11500.abstract   
      
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