A3
6099
Disclaimer — This paper partially fulfills a writing requirement for first year (freshman) engineering students at the
University of Pittsburgh Swanson School of Engineering. This paper is a student, not a professional, paper. This paper is
based on publicly available information and may not be provide complete analyses of all relevant data. If this paper is used
for any purpose other than these authors’ partial fulfillment of a writing requirement for first year (freshman) engineering
students at the University of Pittsburgh Swanson School of Engineering, the user does so at his or her own risk.
COMPLEMENTARY α-SHEET PEPTIDES TO POTENTIALLY TREAT
ALZHEIMER’S DISEASE
Hannah Liu (hkl11@pitt.edu, Bursic 2:00), Shane McKeon (sdm63@pitt.edu, Bursic 2:00)
Revised Proposal—Alzheimer’s Disease (AD) is one of the
most common forms of dementia, responsible for 60% to 80%
of cases in the United States [1]. One cause of AD is the
buildup of toxic, insoluble fibrils comprised of beta-amyloid
(Aβ) peptides that create β-amyloid plaque complexes in the
brain [2]. The plaque begins as an Amyloid Precursor
Protein (APP) that is attached to all neurons, which is usually
cleaved into two fragments by regulatory enzymes, promoting
neuronal health [2]. The Aβ peptide is part of the larger of
the two fragments [2]. However, in a brain with AD, the
larger molecule is cut shorter, causing the shorter portion to
contain the Aβ peptide [2]. Once released with the short
fragment, Aβ peptides naturally aggregate to, form oligomers
[2]. The oligomers begin folding, adopting an α-sheet
intermediate structure and physiologically causing a chain
reaction of similar folding amongst other Aβ peptides [3].
These oligomers can connect to neurons, negatively altering
synapse structures before finally maturing into plaque [3].
Dr. Gene Hopping at the University of Washington has
designed a complementary α- sheet protein that can bind to
the α-sheet structure of the Aβ peptides, inhibiting their
development into plaques [3]. Halting Aβ maturation will
lessen the probability that AD symptoms, such as memory loss
and neuron degradation, will manifest in the patient. [3].
Current treatment aims for early diagnosis combined with
drug therapy, which attempts to rectify symptoms like poor
memory and behavioral agitation [5]. Many medications,
however, only produce small improvements while creating
harmful side effects [4]. Continuing research on α-sheet
proteins is imperative as it addresses an underlying cause of
AD as opposed to solely treating symptoms. Development of
this new treatment is necessary as the baby boomer
generation is reaching the age where they may develop AD,
causing this innovation’s demand to increase exponentially
[4]. Thus, a more beneficial and long-term solution must be
explored.
There are ethical concerns, however, with AD treatment
regarding informed consent, as patients with AD have an
impaired ability to make decisions [5]. Trial participation is
usually determined by family members, who are responsible
for considering the risks and benefits of involvement, leaving
little room for the patient's’ own opinions [5].
We plan to continue researching the mechanisms behind
APP to Aβ plaque transition on a molecular and physical
University of Pittsburgh Swanson School of Engineering 1
2016/01/29
level. We will find more information supporting Dr.
Hopping’s research and how the designed α- sheet peptide
binds to Aβ proteins. Our paper will be organized with a
description of AD, an outline of the process of plaque
formation, an explanation of the role an α-sheet peptide will
play in inhibiting AD progression, and the innovation’s
ethical/societal implications compared to other treatments.
REFERENCES
[1] “What Is Alzheimer’s.” (2016). Alzheimer’s Association.
(online
website).
http://www.alz.org/alzheimers_disease_what_is_alzheimers.
asp
[2] “Alzheimer’s Disease: Unraveling the Mystery.”
(September 2008). National Institute on Aging. (online
article).
https://www.nia.nih.gov/alzheimers/publication/part-2-whathappens-brain-ad/hallmarks-ad
[3] G. Hopping et al. (2014 July 15). “Designed α-sheet
peptides inhibit amyloid formation by targeting toxic
oligomers.” eLIFE. DOI: 10.7554/eLife.01681
[4] C. Belzil. (2007). “Alzheimer’s Dementia.” Lethbridge
Undergraduate Research Journal. (online article).
https://lurj.org/issues/volume-1-number-2/alzheimers
[5] S.Y.H. Kim et al. (2009 Jan 13). “Surrogate consent for
dementia research.” American Academy of Neurology. (online
article). DOI: 10.1212/01.wnl.0000339039.18931.a2
ANNOTATED BIBLIOGRAPHY
“Alzheimer’s Disease: Unraveling the Mystery.” (September
2008).
National Institute on Aging. (online article).
https://www.nia.nih.gov/alzheimers/publication/part-2-whathappens-brain-ad/hallmarks-ad
Published by the NIH, the largest biomedical research
agency, and within the National Institute on Aging, this article
explains the specific proteins, sAPP-α and APP, that are
removed incorrectly, develop into Aβ plaque, and disrupt
neurological function. The information from this article will
be used to visually illustrate and clearly explain the steps from
APP removal to Aβ protein aggregation in AD affected brain
as compared to a healthy brain.
Hannah Liu
Shane McKeon
From the peer-reviewed journal Accounts of Chemical
Research and published by the American Chemical Society,
this article describes how carbonyl and amide groups of an αsheet protein bond and create a polar pleated sheet. This
process allows for simple, self-assembled Aβ plaques. This
information will be used to explain how Aβ peptides
transform from α- to β- sheet structure and why it is
energetically favorable, leading to plaque.
R.S. Armen, M.L. DeMarco, D.O.V. Alonso, and V. Daggett.
(2004 June 10). “Pauling and Corey's α-pleated sheet
structure may define the prefibrillar amyloidogenic
intermediate in amyloid disease.” PNAS. DOI:
10.1073/pnas.0401781101
This article, from PNAS, a peer-reviewed journal, gives a
detailed explanation of how and why Aβ proteins adopt αsheet structures and develop into mature fibrils with β-sheet
structures. We will use this information to include a technical
description of how the aggregation of oligomers causes αsheet folding, why this process allows easy transformation
into plaques, and the properties of intermediate oligomers that
allow an α-sheet protein to bind.
J. Hardy and D.J. Selkoe. (2002 July 19). “The Amyloid
Hypothesis of Alzheimer's Disease: Progress and Problems
on the Road to Therapeutics.” Science. (online article). DOI:
10.1126/science.1072994
This article from a peer-reviewed journal, Science,
explains the amyloid cascade hypothesis which states that
APP gene mutations favor processing by β- or γ- secretase
enzymes, leading to improper removal of Aβ peptides. This
information will be used to explain the primary cause of
incorrect cleavage of APP, eventually resulting in plaque
formation.
C. Belzil. (2007). “Alzheimer’s Dementia.” Lethbridge
Undergraduate Research Journal. (online article).
https://lurj.org/issues/volume-1-number-2/alzheimers
This article from the peer-reviewed journal of Lethbridge
University gives an overview of AD, including causes,
current treatments, and social/ethical issues concerning the
disease and corresponding research. This information will be
used to explain the opposition towards AD research and the
reasons behind an increased demand for new and effective
treatment options, supporting the research to be explained in
our paper.
G. Hopping, J. Kellock, R.P. Barnwal, P. Law, J. Bryers, G.
Varani, B. Caughey, and V. Daggett. (2014 July 15).
“Designed α-sheet peptides inhibit amyloid formation by
targeting
toxic
oligomers.”
eLIFE
.
DOI:
10.7554/eLife.01681
From the peer-reviewed journal, eLIFE, this paper by Dr.
Hopping describes his research on an α-sheet peptide that
binds to toxic oligomers. Specifics like Aβ peptide molecular
composition and its affinity for similar peptides are outlined
and will be used to detail Aβ plaque formation. Also included
are experimental data, testing the efficacy of various α-sheet
peptides compared to others, which we will use as support for
this new treatment.
T.D. Bird. (2015 Sept. 24). “Alzheimer Disease Overview.”
GeneReviews.
(online
article).
http://www.ncbi.nlm.nih.gov/books/NBK1161/
From the peer reviewed journal, GeneReviews, this paper
gives a detailed description of AD causes, diagnosis, and
treatments. Highlighting the importance of early diagnosis,
the article discusses the controversy behind surrogate-consent
when the individual with AD becomes less lucid and family
members must make the primary decisions concerning the
individual’s care. This information elucidates ethical
concerns about AD treatment, a necessary aspect to be
considered in analysis of this innovation.
S.Y.H. Kim, H.M. Kim, K.M. Langa, J.H. Karlawish, D.D.
Knopman, and P.S. Appelbaum. (2009 Jan. 13). “Surrogate
consent for dementia research.” Neurology. (online article).
DOI: 10.1212/01.wnl.0000339039.18931.a2
This peer-reviewed article, published by the American
Academy of Neurology, analyzes surveys from older
Americans, highlighting the significance of patient consent to
partake in any treatment. Since individuals with AD have
impaired decisional capacity, most of their decisions originate
from family members, raising ethical concerns. The article
expands upon the debate between surrogate-consent and
individual-consent—information that will provide a holistic
view of AD treatment options and their ethical/societal
impact.
“Choosing a Topic”. (2016). University of Pittsburgh,
Libguides.
(online
video).
http://www.library.pitt.edu/other/files/il/fresheng/index.html
This instructional video, by the University of Pittsburgh,
explains how to choose a topic in the engineering field. It
delineates the importance of narrowing a general field down
to a specific topic, allowing for a detailed analysis. Choosing
a broad topic will make it difficult to give the paper focus and
research results may be overwhelming. This video helped us
confirm that our topic was appropriate for a sophisticated
paper.
M. Ma. (2014 Jul. 28). “New Protein structure could help treat
Alzheimer’s, related diseases.” University of Washington
Today.
(online
university
newspaper).
http://www.washington.edu/news/2014/07/28/new-proteinstructure-could-help-treat-alzheimers-related-diseases/
V. Daggett. (2006 Jul. 22). “α-Sheet: The Toxic Conformer
in Amyloid Diseases?” Acc. Chem. Res. (online article). DOI:
10.1021/ar0500719
2
Hannah Liu
Shane McKeon
Published in the University of Washington’s newsletter by
Dr. Daggett, this article introduces the α- sheet peptide and
how it will bind to a Aβ peptide. Dr. Daggett works with Dr.
Hopping on building the new protein that will block transition
of Aβ peptides to plaque, illustrated in multiple figures. This
information is the basis of our paper and will provide a
general understanding of the peptide for the introduction.
“What Is Alzheimer’s.” (2016). Alzheimer’s Association.
(online website).
http://www.alz.org/alzheimers_disease_what_is_alzheimers.
asp
This article, written by the national Alzheimer's
Association, provides concise information about the
biological causes of Alzheimer’s. The article describes the
symptoms of AD, how the disease progresses, and the
abnormal interactions between neurons that cause the
degenerative disease. Information from this article will
provide us with a basic understanding of AD that can be used
to introduce the disease in the abstract and introduction.
3