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SUMMARY:Apolipoprotein E and Alzheimer's Disease: Molecular Mechanisms - P
 aul Hopkins\, Kings College London
DTSTART:20120516T110000Z
DTEND:20120516T120000Z
UID:TALK37447@talks.cam.ac.uk
CONTACT:Shannon Tinley-Browne
DESCRIPTION:We previously identified TMCC2 as a protein that shows differe
 ntial interactions with normal versus Alzheimer’s disease-risk versions 
 of both apolipoprotein E (apoE) and the amyloid protein precursor (APP).  
 TMCC2 bound differentially to apoE3 compared to apoE4 and formed a complex
  with APP.  In cultured cells TMCC2 stimulated apoE-dependant Abeta produc
 tion from the “Swedish” variant of APP but not from normal APP\, i.e. 
 facilitated the cellular proteolysis of APP by gamma-secretase.  \nTo addr
 ess the in vivo functions of this novel protein family we investigated the
  Drosophila orthologue of TMCC2\, that we have called Dementin. Ectopic ex
 pression of Dementin rescued developmental and behavioral defects caused b
 y expression of human APP\, and either knockdown or mutation of Dementin l
 ead to developmental lethality and severe neuroanatomical defects.\nWe fur
 ther identified a mutation in the Dementin gene (dmtn1) that leads to part
 ial loss of the putative regulatory region of the protein. Dmtn1 dominantl
 y modified APPL metabolism\, leading to an excess production of C-terminal
  fragments. Adult flies with expression of dmtn1 in neurons only showed pa
 thological features resembling those found in early onset Alzheimer’s di
 sease\, i.e. disrupted metabolism of APPL\, synaptic pathology\, mis-local
 ized microtubule-binding proteins\, neurodegeneration\, and early death. \
 nThus\, molecular\, cellular and genetic evidence show that the interactio
 n between the dementin and APP protein families is evolutionarily conserve
 d\, and further predicts that disrupted function of the mammalian ortholog
 ues of dementin would lead to neurodegeneration.\n
LOCATION:Brain Repair Centre\, Forvie Site\, Robinson Way
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