The Formation of Alzheimer*s Plaques in Synthetic

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Transcript The Formation of Alzheimer*s Plaques in Synthetic

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 Dynamics
McMaster University, Hamilton ON
CAP 2015, University of Alberta, Edmonton AB
ALZHEIMER’S IN THE BRAIN
Alzheimer’s is a type of dementia that
causes problems with memory,
thinking and behaviour.
100μm
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One of the hallmarks of Alzheimer’s
disease are Amyloid-Beta plaques
that are neurotoxic.
Brain of Alzheimer’s patient
Amyloid-β (1-42)
50μm
Neurotoxic plaque
made of amyloid-beta
aggregates
Amyloid-β (25-35)
PROTEIN-PROTEIN INTERACTIONS
Negative
Curvature
Membrane mediated
elastic interaction
Positive
Curvature
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?

1.
2.
3.
4.
Alzheimer’s plaques depend on
Cholesterol level
Diet
Hormones
Protein concentration
http://webneel.com/
2. What is the structure of these plaques?
o Microscopy (Surface)
o X-ray diffraction (Inside)
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
Amyloid-ß (1-42)
Hydrophobic
tails
Amyloid-ß (25-35)
DMPS is charged
Hydrophilic
head groups
SYNTHETIC MEMBRANE PREPARATION
Multi-lamellar, solid supported
synthetic membranes
MICROSCOPY
0.1mm
0.1mm
POPC/DMPS
POPC/DMPS 20%Aβ
No plaques formed
0 mol%
Plaques formed
At 10 mol%,
plaques start
appearing
20 mol%
PLAQUE SIZE AND DENSITY
Average plaque size: 11.05 µm
Average plaque size: 10.91 µm
59 ± 3 plaques/mm2
920 ± 64 plaques/mm2
Plaque size is independent of protein concentration
MOLECULAR STRUCTURE USING X-RAYS
PEPTIDE SIGNALS
10% Amyloid-Beta
20% Amyloid-Beta
50% : 50%
ANGULAR DISTRIBUTION
Membrane
Curvature
b-Sheets
a-Helices
Membrane Tails
ORIENTATION AND INTENSITY
PROPOSED PLAQUE MODEL
• 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
11 mm
CONCLUSIONS
•
•
Alzheimer's senile plaques form in synthetic
membranes concentrations 10mol% or more
Two distinct protein conformations (a-helices and
b-sheets)
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Alzheimer’s patient
•
Synthetic Alzheimer’s Membrane
Synthetic membranes may be used as
model system for in vitro drug testing in
the future.
ACKNOWLEDGEMENTS
NETLOGO SIMULATION
Short range
interaction
Long range
interaction
REFLECTIVITY MEASUREMENTS:
FROM RECIPROCAL SPACE TO REAL SPACE
Bragg’s Law:
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