LONDON- The successful creation of a new transgenic mouse
carrying a gene for human Alzheimer's disease should offer
researchers an important new research tool in the search for
useful treatments for what is currently an incurable disease.
Many researchers consider the deposition of a starch-like
protein called beta- amyloid in the brains of Alzheimer's
patients to be the key to understanding the disease. Genetic
researchers have identified pathogenic mutations in a gene which
encodes the b-amyloid precursor protein (APP). Alterations in
this gene lead to altered processing of APP and increased
deposition of the potentially pathogenic beta-amyloid deposits.
The researchers took a new approach to a problem that has
challenged science for years, the development of a transgenic
Alzheimer's mouse. The investigators created a construct composed
of the full length human APP complementary DNA with the APP
mutation under the control of a factor called platelet-derived
growth factor (PDGF) promoter. They inserted selected introns
from the APP gene important for the splicing of the gene product
into this construct. In other words, they constructed a
combination of complementary DNA and a genomic construct. The DNA
element helps activate the gene in the parts of the brain
affected by Alzheimer's disease, the hippocampus and the cerebral
cortex. This gene construct was then inserted into mouse embryos
using microinjection techniques.
No neurological changes were seen in the mice in the first
six months of life. However, between six and nine months the
transgenic animals developed many of the characteristics of the
brains of patients with Alzheimer's disease. These included the
deposition of beta-amyloid plaque, neuritic damage and reduction
in synapse density. As the animals aged the amyloid plaque
deposits continued to increase in size, resembling human
pathology. Non transgenic littermates showed none of these
The next step will be to breed large number of the mice and
observe them for signs of cognitive changes associated with
Alzheimer's including memory loss. The researchers will also want
to determine what elements of the construct allowed the
experiment to succeed- the promoter, the use of introns and/or
Alzheimer's research has been limited by the lack of a
reliable animal model. The development of the Alzheimer's mouse
will help researchers understand the pathology of the disease.
First, the creation these transgenic animals may finally answer
the question of whether the amyloid plaques do cause Alzheimer's
disease. Second, the transgenic mice in the current experiment
developed most of the pathologic changes seen in human brains
with the exception of neurofibrillary tangles. This observation
alone may cause a reconsideration of the pathogenesis of the
disease, suggesting that these tangles are a result of a
destructive neurological process rather than a cause.
The new transgenic mouse should also speed the development
of drugs for treating Alzheimer's in humans. Researchers will be
able to screen large numbers of drugs in the animal model before
proceeding to human trials with any promising agents.
Alzheimer's disease is the fourth leading cause of death in
the developed world, after heart disease, cancer, and stroke.
Alzheimer's disease strikes some four million Americans, at a
cost to the nation of $100 billion. The disease is named for
Alois Alzheimer, the German neurologist who first described the
pathology of the disease nearly 100 years ago.
The details of the Alzheimer's mouse research can be found
in Nature, v.373, 2/9/95, Games et al. pp. 523-537 and pp.