T HE F ORMATION OF A LZHEIMER ’ S P LAQUES IN S YNTHETIC M EMBRANES Jennifer Tang, Richard Alsop,...
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Transcript of T HE F ORMATION OF A LZHEIMER ’ S P LAQUES IN S YNTHETIC M EMBRANES Jennifer Tang, Richard Alsop,...
THE FORMATION OF ALZHEIMER’S PLAQUES IN SYNTHETIC MEMBRANES
Jennifer Tang, Richard Alsop, Matilda Backholm, Hannah Dies, and Maikel C. Rheinstädter
Laboratory for Membrane and Protein DynamicsMcMaster University, Hamilton ON
CAP 2015, University of Alberta, Edmonton AB
ALZHEIMER’S IN THE BRAIN
Neurotoxic plaque made of amyloid-beta aggregates
Alzheimer’s is a type of dementia that causes problems with memory, thinking and behaviour.
One of the hallmarks of Alzheimer’s disease are Amyloid-Beta plaques that are neurotoxic.
Brain of Alzheimer’s patient Amyloid-β (1-
42)
Amyloid-β (25-35)
50μm
kurzweilai.net
100μm
PROTEIN-PROTEIN INTERACTIONS
Positive Curvature
Negative Curvature
Membrane mediated elastic interaction
The curvature of the membrane depends on membrane composition which affects the plaque formation
properties
RESEARCH QUESTIONS
1. Do Alzheimer's plaques form in synthetic membranes? If so, under what conditions do they form?
2. What is the structure of these plaques?oMicroscopy (Surface)o X-ray diffraction (Inside)
Alzheimer’s plaques depend on
1. Cholesterol level
2. Diet
3. Hormones
4. Protein concentration http://webneel.com/
SYNTHETIC “ALZHEIMER’S MEMBRANES”
Saturated: 50mol% Unsaturated: 50 mol% Charged: 3 mol%-Amyloid-b: 1-3mol%
POPC has one saturated tail and one unsaturated tail
DMPS is charged
Hydrophobic tails
Hydrophilic head groups
SYNTHETIC MEMBRANE PREPARATION
Multi-lamellar, solid supported synthetic membranes
MICROSCOPY
POPC/DMPS POPC/DMPS 20%Aβ
No plaques formed
Plaques formed
0.1mm
0.1mm
At 10 mol%, plaques
start appearing
0 mol% 20 mol%
PLAQUE SIZE AND DENSITY
Average plaque size: 11.05 µm
59 ± 3 plaques/mm2
Average plaque size: 10.91 µm
920 ± 64 plaques/mm2
Plaque size is independent of protein concentration
MOLECULAR STRUCTURE USING X-RAYS
PEPTIDE SIGNALS10% Amyloid-Beta
20% Amyloid-Beta
50% : 50%
ANGULAR DISTRIBUTION
Membrane Tailsa-Helices
b-Sheets
Membrane Curvature
ORIENTATION AND INTENSITY
PROPOSED PLAQUE MODEL
11 mm
• One type of plaque found in 10mol% and 20mol% samples with diameter ~11 µm
• Plaques are embedded in membranes
• Contain a mixture of a and b-peptides
CONCLUSIONS
Alzheimer’s patient Synthetic Alzheimer’s Membrane
• Alzheimer's senile plaques form in synthetic membranes concentrations 10mol% or more
• Two distinct protein conformations (a-helices and b-sheets)
• Synthetic membranes may be used as model system for in vitro drug testing in the future.
kurzweilai.net
100μm
ACKNOWLEDGEMENTS
NETLOGO SIMULATION
Short range interaction
Long range interaction
REFLECTIVITY MEASUREMENTS:FROM RECIPROCAL SPACE TO REAL SPACE
Fourier analysis to determine electron density:
• ρ(z) is the electron density perpendicular to the plane of the membrane
• ρw is the electron density of water (0.22 e/A3 )
• F is the form factor• I is the integrated intensity of a Bragg
peak• v is the phase (+/- 1)• dz is the spacing of the bilayers
Bragg’s Law: