Alzheimer's, Dementia & Mental Health
New Lab Rat May Be Star of Future Alzheimer’s
Research; Confirms Beta-Amyloid as Cause
New research funded by National Institutes of Health
confirms Alzheimer’s brains have abnormal levels of beta-amyloid protein
that form amyloid plaques
April 19, 2013 – Recent announcements from the
National Institutes of Health about Alzheimer’s research almost sounded
routine. On a second look, however, the confirmation that increases in
the molecule beta-amyloid in the brain causes the disease, and that a
new genetically engineered lab rat has been created with the full array
of brain changes found in the disease.
Beta-amyloid molecules (green) surround dying
neurons (red) in the brains of a new rat model of Alzheimer’s disease.
Courtesy of Town lab, Zilkha Neurogenetic Institute at the University of
Southern California Keck School of Medicine.
“We believe the rats will be an excellent,
stringent pre-clinical model for testing experimental Alzheimer’s
disease therapeutics,” said Terrence Town, Ph.D., senior author of the
study funded by NIH and published in the Journal of Neuroscience.
Dr. Town is a professor in the Department of
Physiology & Biophysics in the Zilkha Neurogenetic Institute at the
University of Southern California Keck School of Medicine, Los Angeles.
Alzheimer’s is an age-related brain disorder that
gradually destroys a person’s memory, thinking, and the ability to carry
out even the simplest tasks. Affecting at least 5.1 million Americans,
the disease is the most common form of dementia in the United States.
Pathological hallmarks of Alzheimer’s brains
include abnormal levels of beta-amyloid protein that form amyloid
plaques; tau proteins that clump together inside neurons and form
neurofibrillary tangles; and neuron loss. Additionally, glial cells —
which normally support, protect, or nourish nerve cells — are
overactivated in Alzheimer’s.
Plaque-forming beta-amyloid molecules are derived
from a larger protein called amyloid precursor protein (APP). One
hypothesis states that increases in beta-amyloid initiate brain
degeneration. Genetic studies on familial forms of Alzheimer’s support
the hypothesis by linking the disease to mutations in APP, and to
presenilin 1, a protein thought to be involved in the production beta-amyloid.
Researchers often use rodents to study diseases.
However, previous studies on transgenic mice and rats that have the APP
and presenilin 1 mutations only partially reproduce the problems caused
by Alzheimer’s. The animals have memory problems and many plaques but
none of the other hallmarks, especially neurofibrillary tangles and
To address this issue, Dr. Town and his colleagues
decided to work with a certain strain of rats.
“We focused on Fischer 344 rats because their
brains develop many of the age-related features seen in humans,” said
Dr. Town, who conducted the study while working as a professor of
Biomedical Sciences at Cedars-Sinai Medical Center and David Geffen
School of Medicine at the University of California, Los Angeles.
The rats were engineered to have the mutant APP and
presenilin 1 genes, which are known to play a role in the rare,
early-onset form of Alzheimer’s. Behavioral studies showed that the rats
developed memory and learning problems with age. As predicted, the
presence of beta-amyloid in the brains of the rats increased with age.
However, unlike previous rodent studies, the rats also developed
“This new rat model more closely represents the
brain changes that take place in humans with Alzheimer’s, including tau
pathology and extensive neuronal cell death,” said Roderick Corriveau,
Ph.D., a program director at NIH’s National Institute of Neurological
Disorders and Stroke. “The model will help advance our understanding of
the various disease pathways involved in Alzheimer’s onset and
progression and assist us in testing promising interventions.”
The researchers performed a variety of experiments
confirming the presence of neurofibrillary tangles in brain regions most
affected by Alzheimer’s such as the hippocampus and the cingulate
cortex, which are involved in learning and memory. Further experiments
showed that about 30 percent of neurons in these regions died with age,
the largest amount of cell death seen in an Alzheimer’s rodent model,
and that some glial cells acquired shapes reminiscent of the activated
glia found in patients.
“Our results suggest that beta-amyloid can drive
Alzheimer’s in a clear and progressive way,” said Dr. Town.
Activation of glia occurred earlier than amyloid
plaque formation, which suggests Dr. Town and his colleagues identified
an early degenerative event and new treatment target that scientists
studying other rodent models may have missed.
The findings support a prime research objective
identified during the May 2012, NIH-supported
Disease Research Summit 2012: Path to Treatment and Prevention,
an international gathering of Alzheimer’s researchers and advocates.
Improved animal models were cited as key to advancing understanding of
this complex disease.
"To fully benefit from this exciting new work,
there is a critical need to share the animal model with researchers
dedicated to finding ways to delay, prevent or treat Alzheimer's
disease’’ said Neil Buckholtz, Ph.D., of the National Institute on
Aging, which leads the NIH effort in Alzheimer’s research. “Accordingly,
Dr. Town and his colleagues are working towards making their new rat
model easily accessible to the research community.”
In addition to grants from NINDS (NS076794), NIA
(AG029726, AG033394) and the NIMH Intramural Research Program, this
study was funded by the Alzheimer’s Association (IIRG-05-14993,
ZEN-10-174633) and the Ellison Foundation/American Federation for Aging
For more information about Alzheimer’s disease,
is the nation’s leading funder of research on the brain and nervous
system. The NINDS mission is to reduce the burden of neurological
disease — a burden borne by every age group, by every segment of
society, by people all over the world.
About the National Institutes of Health (NIH): NIH,
the nation's medical research agency, includes 27 Institutes and Centers
and is a component of the U.S. Department of Health and Human Services.
NIH is the primary federal agency conducting and supporting basic,
clinical, and translational medical research, and is investigating the
causes, treatments, and cures for both common and rare diseases. For
more information about NIH and its programs, visit
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