UCI Resarchers Create First Living Model to Exhibit

Unique triple-transgenic mouse offers chance to develop single class of drugs

Irvine, Calif. — A newly engineered, genetically altered mouse will allow researchers for the first time to study the two signature lesions of Alzheimer’s disease in a single organism — a model that closely matches how the disease develops in the human brain.

Created by UC Irvine neurobiologists Frank LaFerla and Salvatore Oddo, the mouse is expected to provide a better “living laboratory” for understanding how these lesions grow, aiding efforts to find an effective treatment for both the sporadic and inherited forms of the disease.

“For the first time, plaque and tangle lesion formations can be studied together, letting us understand the relationship between the two lesions and dissect the processes by which they may be connected,” said LaFerla, a professor of neurobiology and behavior, and senior author of the study, which appears in the July 31 issue of Neuron.

Plaque lesions grow on the outside of healthy cells, cutting off their ability to communicate with other cells, while tangle lesions grow inside of neural cells and clog signaling pathways. Plaque lesions are factors in the early-onset inherited and sporadic forms of the disease, and tangle lesions are found primarily in the sporadic form.

According to LaFerla, the mouse will be valuable in the search for drugs that can target both lesions. “This may eventually lead to a single class of drugs for treating both the inherited and sporadic forms of the disease,” he said. “We now have the ability to study a wider spectrum of Alzheimer’s disease than previously possible.”

LaFerla and Oddo created the mouse by genetically altering it to host three mutant human genes that foster lesion growth: beta-amyloid precursor protein (âAPP), presenilin-1 and tau. âAPP is the source of the beta-amyloid protein that forms into brain plaques, while presenilin-1 is needed for this protein to form. Tau is the critical component of tangles.

Using the triple-transgenic mouse, the UCI researchers have already traced the sequence of molecular events leading to the disease. Significantly, they found that beta-amyloid plaques appeared first in the mouse brain, and tau-laden tangles appeared later. This suggests that beta-amyloid may be the initiating component of both sporadic and familial Alzheimer’s disease.

“This finding confirms the human genetic data indicating that plaques are the earliest pathological feature of the disease,” said LaFerla. The UCI researchers also found that beta-amyloid can accumulate in neural cells before plaques or tangles form. This appears to diminish the function of brain synapses, which may lead to memory impairments, the signature feature of Alzheimer’s disease. The researchers found this was the earliest pathological change that occurred in their mice and will further investigations into the condition in humans.

Alzheimer’s disease is the most common cause of dementia, afflicting more than four million Americans. The majority of Alzheimer’s cases are sporadic, striking individuals at random as opposed to running in families. Generally, the sporadic form afflicts individuals older than 65. A small percentage of cases are passed down from one generation to another and generally have a much earlier onset, usually in the 40s or 50s, but sometimes as young as 16 years of age. Other than the age of onset, both forms are fairly similar.

The National Institute for Aging and the Alzheimer’s Association funded the research.

About the triple-transgenic mouse

Transgenic mice have enabled researchers to observe experimentally what happens to an entire organism during the progression of a disease. In many areas, they are already the leading models for studying human diseases and their treatments.

To create these mice, UCI researchers injected foreign genetic material (generally, human genes harboring disease-causing mutations) into fertilized mouse eggs. When the mice were born, the ones producing the human proteins typically developed the designated traits or disease phenotype, and in the case for the mice in this study, the Alzheimer-type pathology.

Because mice don’t normally develop Alzheimer’s pathology, the only way to reproduce it in mice was to have them overproduce the human proteins associated with the disease. LaFerla and Oddo created the model for this study by injecting âAPP and tau genes into single-cell embryos from single-transgenic mice already harboring the presenilin-1 gene. This method assured that future generations would inherit the genetic material as one unit.

Because of this, the mice will be easy to breed and have the same genetic background. This is an important feature for analyzing the behavior of these mice and for evaluating drugs, since the researchers won’t have to worry about the confounding effects associated with mice with different genetic backgrounds. It is anticipated that this unique mouse model will prove to be extremely useful in the preclinical evaluation of potential Alzheimer drugs.

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