mg-262 and Alzheimer-Disease

Analysis of brain microtubule protein from patients with Alzheimer's disease showed decreased alpha tubulin levels along with increased acetylation of the alpha tubulin subunit, mainly in those microtubules from neurons containing neurofibrillary tau pathology. To determine the relationship of tau protein and increased tubulin acetylation, we studied the effect of tau on the acetylation-deacetylation of tubulin. Our results indicate that tau binds to the tubulin-deacetylase, histone deacetylase 6 (HDAC6), decreasing its activity with a consequent increase in tubulin acetylation. As expected, increased acetylation was also found in tubulin from wild-type mice compared with tubulin from mice lacking tau because of the tau-mediated inhibition of the deacetylase. In addition, we found that an excess of tau protein, as a HDAC6 inhibitor, prevents induction of autophagy by inhibiting proteasome function.

Topics: Acetylation; Aged; Aged, 80 and over; Alzheimer Disease; Animals; Boronic Acids; Brain; Cells, Cultured; Embryo, Mammalian; Enzyme Inhibitors; Female; Gene Expression Regulation; Histone Deacetylase 6; Histone Deacetylases; Humans; Immunoprecipitation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microtubule-Associated Proteins; Neurons; Postmortem Changes; tau Proteins; Transfection; Tubulin

Impairment of the ubiquitin/proteasome system has been proposed to play a role in neurodegenerative disorders such as Alzheimer and Parkinson diseases. Although recent studies confirmed that some disease-related proteins block proteasomal degradation, and despite the existence of excellent animal models of both diseases, in vivo data about the system are lacking. We have developed a model for in vivo analysis of the ubiquitin/proteasome system by generating mouse strains transgenic for a green fluorescent protein (GFP) reporter carrying a constitutively active degradation signal. Administration of proteasome inhibitors to the transgenic animals resulted in a substantial accumulation of GFP in multiple tissues, confirming the in vivo functionality of the reporter. Moreover, accumulation of the reporter was induced in primary neurons by UBB+1, an aberrant ubiquitin found in Alzheimer disease. These transgenic animals provide a tool for monitoring the status of the ubiquitin/proteasome system in physiologic or pathologic conditions.

Topics: Alzheimer Disease; Animals; Boronic Acids; Cells, Cultured; Cysteine Endopeptidases; Fibroblasts; Leupeptins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Fluorescence; Models, Animal; Multienzyme Complexes; Myocytes, Cardiac; Neurodegenerative Diseases; Neurons; Oligopeptides; Organ Specificity; Parkinson Disease; Proteasome Endopeptidase Complex; Recombinant Fusion Proteins; Tissue Distribution; Ubiquitin