Understanding Alzheimer’s Disease:
Molecular Analysis of A-beta Accumulation
Jayanth (Jay)
1,2
Krishnan ,
Catherine (Cat)
1,2
Mahoney
1
Rensselaer Polytechnic Institute - Department of Biology ; 2Barton Hal 3414 - 1999 Burdett Avenue - Troy, NY 12180-3599
Introduction - Abstract
Alzheimer’s disease was officially diagnosed
in a patient in 1906 by Alois Alzheimers and
named in 1910 by Emil Kraepelin. The disease
causes a loss in brain function and gradually
exacerbate over time. It adversely affects
memory, thinking, and behavior.
AD is considered a monumental problem in
present day society. A recent census
concluded that 35 million people, including 5
million Americans, have been diagnosed with
the disease. For their treatment, it costs
roughly 600 billion dollars. [3]
Scientists, here at Rensselaer, are interested
in finding a cure for AD by studying the
structural mechanism (of important poly
peptides), nuclear magnetic resonance,
molecular dynamics simulations, biochemistry
and biophysics. These scientists, who work at
the Biotech Center, are researching ways to
eradicate Alzheimer's Disease by studying the
aggregation of a specific protein named Abeta.
By understanding how Abeta binds, the drug
perturbation industry for AD may ameliorate.
Inspiration
Three eminent professors at the Biotech
center inspired us to study more extensively
about A-Beta and AD. We heard these
professors present their research/results at
the 2nd Biotechnology Public Interest Forum.
The speakers included Dr. Chunyu Wang, Dr.
Wilfredo (Freddie) and Dr. Peter Tessier.
Primary Objective
The professors research focused on several
aspects of AD that dealt with the structural
mechanism of Amyloid beta (Aβ or Abeta),
which is a peptide of 36 –43 amino acids
processed by the Amyloid precursor protein
known to be associated with both types of AD.
The disease can either be sporadic or familial
and is caused by mutations. Study of Abeta’s
structure shall hopefully aid in drug prediction
and eradicate AD.
RESEARCH POSTER PRESENTATION DESIGN © 2011
www.PosterPresentations.com
Figures
Conclusions
1) The increased ratio Abeta42 to
Abeta40 is characteristic of AD. This can
contribute to drug prediction to prolong
the effects of AD. A drug with Abeta40
may be the cure for AD
Structural and Molecular Representations
of Amyloid Beta [1], [2]
2) Abeta and Cyclophilin D interact
causing harmful effects. The study of
how they interact can offer insights for
pharmaceutical perturbation of drugs
Results
Associate Professor of Biology, Dr. Chunyu Wang focused on Abeta40 and Abeta42 (The Yin and Yang
of AD). Although these peptides might only vary by two amino acids, their structural components are
much more different. Wang realized that a patient with AD had an increased ratio of Abeta42 to
Abeta40. It is predicted that aggregation of Abeta42 causes increased familial AD and that Abeta40
may eventually prevent and cure AD. Wang wanted to further tackle how the structure of Abeta42 is
related to toxicity and memory loss. Using silicon screening, both structures have been mapped out.
Wang then knew that Abeta and Cyclophilin D join together causing harmful molecules to leak out in
a process called mitochondrial dysfunction. Hence, he is currently leading projects on how Abeta and
Cyclophilin D interact. Only four drugs are currently on the market based on the acetylcholine
receptor. With Wang’s research, perhaps more drugs can be put out.
Associate Professor of Chemistry and popular General Chemistry Lecturer, Dr. Wilfredo (Freddie)
Colon focused on Abeta accumulation. He believes that the disease needs to be delayed not cured
and wants to know why Abeta accumulates. Currently, scientists do not know what triggers
accumulation in 95% of AD. Dr. Colon believes that the protein degradation machinery is compromised
causing Abeta toxic species to be difficult to degrade. Some factors that might compromise the
protein degradation system of an individual include aging, genetic factors, external factors such as
damage caused by exposure or inflation, overproduction of Abeta, and deficiencies in the
metabolism.
However, some toxic A-beta species may be resistant to degradation due to kinetic stability – this has
to do with being trapped. Abnormal loss or gain of kinetic stability can result in AD, Parkinson’s
disease, or even Mad Cow disease. Colon hypothesized that the toxic Abeta species that are
kinetically stable might play a pathological role in AD. Hence, he wanted to discover and implement
a biomarker approach.
Dr. Peter Tessier, is the assistant professor of Chemical and Biological Engineering. Dr. Tessier
reviewed some of the general concepts of AD describing it as one of the greatest challenges of our
time and how a neuron with Amyloid plague results in AD. His research focused on how the proteins
were packed, and how different packing arrangements result in either benign formations or toxic
formations. He is currently working on changing the shapes or disassociating the proteins that
aggregate back into monomers.
3) Abeta’s kinetic stability causes it to
refrain from degradation may have a
role in causing AD
4) Disassociation of proteins into
monomers may be the way to cure AD
References
[1] "AMYLOID BETA-PROTEIN (HUMAN, 25-35)
TRIFLUOROACETATE | 131602-53-4."
ChemicalBook---Chemical Search Engine. Web.
05 Dec. 2011.
<http://www.chemicalbook.com/ChemicalPro
ductProperty_EN_CB7297245.htm>.
[2] "Common Properties of Alzheimer’s
Amyloid-beta and a Beta-solenoid Hemoglobin
Protease of E. Coli." Groentech Blog. Web. 05
Dec. 2011.
<http://groentech.blogspot.com/2011/04/com
mon-properties-of-alzheimers-amyloid.html>.
[3] "Alzheimer's Disease - PubMed Health."
Web. 05 Dec. 2011.
<http://www.ncbi.nlm.nih.gov/pubmedhealth
/PMH0001767/>.
Acknowledgements
Dr. Michael Hanna, Dr. Chunyu Wang, Dr
Wilfredo Colon, Dr. Peter Tessier, Ms.
Bianca Pier