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A Probable Treatment for Alzheimer’s Disease:
Somewhere Between Confusion and Clarity
The Transthyretin Protein
Edgewood SMART Team: R. Cray, W. Grosenheider, S. Huntoon, T. Johnson, C. Lee, E. Madsen, C. McLaughlin, M. Popp, J. Power,
K. Ralph, S. Rothrock, N. Sekhon, E. Sharata
Teacher: Mr. Dan Toomey
Mentor: Dr. Jeffrey A. Johnson, University of Wisconsin – Madison, School of Pharmacy
lzheimer’s disease currently affects an estimated 4.5 million Americans. The progressive degenerative neurological
Adisorder
is commonly associated with memory loss and intellectual impairments concerning speech, skilled movements, and
recognition. Discovered in the early 1900s by German psychiatrist Alois Alzheimer, the specific cause of the disease is not known, though
the presence of Alzheimer’s disease has been connected to abnormal folding of the amyloid beta (A-beta) protein in the brain. Today,
Alzheimer’s disease is the eighth leading cause of death in the United States, with over 63,000 fatalities accounted for. Alzheimer’s disease
is also the third most costly disease in the country, costing the U.S. over $100 billion each year.
T
Alois Alzheimer, the German psychiatrist who
discovered Alzheimer’s disease.
he A-beta protein and transthyretin are two proteins of interest to scientists trying to understand how Alzheimer’s disease develops.
The disease results from the accumulation of a specific fragment of the amyloid precursor protein. When this small piece of protein is cut
from the amyloid precursor protein, the smaller piece is referred to as the A-beta protein. The A-beta protein forms plaques by aggregating
together (shown in Figure 1), as well as causing neurons in the brain to die, resulting in Alzheimer’s disease. Transthyretin, however, is the
“good protein” and prevents the A-beta protein from killing those neurons. Though researchers do not specifically know how the
transthyretin does this, it is hypothesized that the transthyretin binds with the A-beta so that it cannot interact with the neurons.
FIGURE 1
tudies have shown that mice genetically engineered to have higher levels of the A-beta protein also have
more
transthyretin, therefore preventing Alzheimer’s-like pathology from occurring in the mice. Shown below in Figure 2 are
examples from the mouse experiment. Boxes C and E are enlarged from Box A to show portions of the hippocampus (a part
of the brain found in the temporal lobe concerned with memory) of the control mouse. Boxes D and F show the enlarged
portions of the hippocampus of the mouse that over expressed the mutant amyloid precursor protein and had high levels of Abeta. The brown areas shown in Figure 2 in boxes
B, D, and F represent the presence of the transthyretin protein, showing
FIGURE 2
how much the mouse’s brain has increased transthyretin levels to protect
CONTROL
APP MICE
itself from the induced A-beta increases and neuronal cell death. This
increase in transthyretin, unfortunately, only happens in mice, and has
not been seen in humans living with Alzheimer’s disease. Because mice
have dramatically increased transthyretin levels, which block the A-beta
toxicity, researchers are trying to find ways of increasing that protein in
humans.
S
The comparison of a healthy brain cell and a
brain cell with Alzheimer’s disease.
Inc., is a biopharmaceutical company
Mithridion,
founded by Dr. Jeffrey Johnson and his colleagues,
Comparison of transthyretin levels in the brain between the control
mouse and the mouse with genetically increased A-beta levels.
with the mission of discovering and developing new drugs
to treat Alzheimer’s and other neurodegenerative diseases
(Figure 3). Having patented findings from the mouse
experiment, Mithridion, Inc., aims to develop a drug that
will mimic the protein in a mouse’s brain, sAPPalpha, not
found in humans, that causes increased transthyretin levels
in the mouse brain. This drug could protect humans from
the toxicity of A-beta and stop the progression of
Alzheimer’s disease. The company hopes to have a drug
available to the public within the next few years.
Supported by the National Institutes of Health (NIH) – National Center for Research Resources Science Education Partnership Award (NCRR-SEPA)
FIGURE 3
M D
K
Neuroprotective
sAPPα
α
A
E
V
T
E
602 amino acids
F
E
E
R
S
H
I
D
S
Neuroprotective fragments
E
DRUG LEAD
K
H
Y
Neuroprotective
tetrapeptide
(4 amino acids)
from sAPPalpha
Q
H
G
V
Transthyretin
protects neurons
from A-beta
toxicity
From Bench to Bedside
Mithridion, Inc. is breaking new ground in Alzheimer’s research and drug development.
Disclosure: Dr. Jeff Johnson has an ownership interest in Mithridion, Inc., which has an exclusive
license of the technology reported in this slide.