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SUMMARY:Protein misfolding in Alzheimer’s disease - Prof. Louise Serpell
 \, University of Sussex\, UK
DTSTART:20200219T103000Z
DTEND:20200219T113000Z
UID:TALK139798@talks.cam.ac.uk
CONTACT:Dr Georg Meisl
DESCRIPTION:Protein misfolding is central to many diseases including Alzhe
 imer's disease. However\, the mechanism by which conformational change is 
 initiated remains elusive. Alzheimer's disease is characterised by key pro
 teins including Tau\, Amyloid-beta and by the risk factor isoform Apolipop
 rotein E4. However\, the role of each of these in the neurodegenerative di
 sease cascade is unclear. Our work aims to explore the initiation events t
 hat lead to misfolding and the downstream effects on neuronal function\, w
 hilst clarifying the potentially toxic species. In this talk\, I will desc
 ribe work that aims to uncover fundamental mechanisms at the heart of the 
 structural changes in Amyloid-beta\, tau and ApoE4.\n\nApoE is the major g
 enetic risk factor for developing AD. Despite decades of research\, the wa
 y in which ApoE exerts its effect remains elusive. We have recently compar
 ed and characterised the three isoforms of ApoE and show that ApoE4 is abl
 e to self-assemble into non-amyloid-like filaments.  Tau is a natively unf
 olded protein which\, unlike Amyloid-beta\, does not readily self-assemble
 . We have developed a model fragment which self-assembles to form paired h
 elical filaments in vitro which we have used to examine cellular mechanism
 s of transmission and toxicity.  Amyloid beta rapidly self-assembles and o
 ligomeric species have been previously shown to affect neuronal health. We
  have studied the uptake and effects on organelles including lysosomes\, s
 ynaptic vesicles and mitochondria to dissect mechanisms that lead to neuro
 nal dysfunction and cell death. We reveal damage to specific organelles of
  the cell which are accompanied by impaired synaptic vesicle release and r
 euptake. We consider the underlying mechanisms that may consolidate these 
 findings and explore potential therapies.
LOCATION:Department of Chemistry\, Cambridge\, Unilever lecture theatre
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