Apolipoprotein E and Alzheimer's Disease: Molecular Mechanisms

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• Paul Hopkins, Kings College London
• Wednesday 16 May 2012, 12:00-13:00
• Brain Repair Centre, Forvie Site, Robinson Way.

If you have a question about this talk, please contact Shannon Tinley-Browne.

We previously identified TMCC2 as a protein that shows differential 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 production from the “Swedish” variant of APP but not from normal APP , i.e. facilitated the cellular proteolysis of APP by gamma-secretase. To address the in vivo functions of this novel protein family we investigated the Drosophila orthologue of TMCC2 , that we have called Dementin. Ectopic expression of Dementin rescued developmental and behavioral defects caused by expression of human APP , and either knockdown or mutation of Dementin lead to developmental lethality and severe neuroanatomical defects. We further identified a mutation in the Dementin gene (dmtn1) that leads to partial loss of the putative regulatory region of the protein. Dmtn1 dominantly modified APPL metabolism, leading to an excess production of C-terminal fragments. Adult flies with expression of dmtn1 in neurons only showed pathological features resembling those found in early onset Alzheimer’s disease, i.e. disrupted metabolism of APPL , synaptic pathology, mis-localized microtubule-binding proteins, neurodegeneration, and early death. Thus, molecular, cellular and genetic evidence show that the interaction between the dementin and APP protein families is evolutionarily conserved, and further predicts that disrupted function of the mammalian orthologues of dementin would lead to neurodegeneration.

This talk is part of the BRC Seminar Series series.

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