UCI Researchers Identify Trigger For Onset Of Alzheimer's, Aiding Search For New Therapies

The trigger is a protein called "beta amyloid" that accumulates within neurons in the mice's brains. Although several researchers have studied the association between beta amyloid and memory, the UCI research team is the first to identify that early beta amyloid accumulation within neurons is the trigger for the onset of memory decline in Alzheimer's.

"This finding has important and useful implications for the pharmaceutical industry in terms of developing drugs that can target beta amyloid as soon as it accumulates within the neurons," said Frank LaFerla, principal investigator of the research project, associate professor of neurobiology and behavior, and co-director of the UCI Institute for Brain Aging and Dementia. "Once the plaques and tangles form, it is too late."

The researchers report their findings in the March 3 issue of Neuron.

Although the production of beta amyloid occurs in all brains, healthy brains are able to clear away excess amounts. Brains with Alzheimer's disease, on the other hand, are unable to control beta amyloid accumulation. In monitoring the mice from birth until six months, the researchers found that the mice had no Alzheimer's disease symptoms at two months of age. At four months, however, the mice showed a decline in their long-term memory retention that the researchers found occurred in combination with the buildup of beta amyloid in neurons of the hippocampus, amygdala and cerebral cortex regions of the mice's brains.

While the hippocampus is thought to play a key role in learning and memory formation, the amygdala is involved in computing the emotional significance of events. The cerebral cortex – the outer portion of the brain – is where thought processes occur.

"It's significant that the plaques and tangles did not show up in our mice at the four-month stage," said Lauren M. Billings, a postdoctoral researcher in the UCI School of Biological Sciences' Department of Neurobiology and Behavior, and the first author of the study. "It suggests strongly that these hallmarks of Alzheimer's disease contribute to cognitive decline only later and that the intraneuronal beta amyloid is the molecular trigger for the onset of this insidious disease."

Billings explained the mice were making more beta amyloid than their brains could clear naturally. When the researchers cleared away the beta amyloid within the neurons, however, they were able to correct the memory impairments in the mice. Moreover, the researchers found that a reemergence of beta amyloid inside the neurons in the mice marked again the onset of memory problems.

In their study, the researchers used mice that were genetically engineered to develop Alzheimer's disease, a necessary step in the research since mice ordinarily do not develop symptoms of the disease. The molecular and cellular changes that trigger the onset of memory decline in the human brain with Alzheimer's disease are currently unknown and constitute a difficult problem to address. Hence, researchers turn to animal models, such as mice.

The UCI researchers studied 270 mice from birth until six months. They placed the mice in a water maze set in a water tank where the mice were encouraged repeatedly to locate a hidden platform in the tank by making spatial associations in the room to facilitate their search. After the platform was removed, the researchers monitored in subsequent trials how fast the mice swam to where the platform used to be – an indication of how well the mice remembered the platform's location. At four months of age, the mice developed memory problems together with beta amyloid accumulation in their brain's neurons.

Alzheimer's disease is a progressive neurodegenerative disorder and the most common cause of dementia among the elderly in the United States, affecting 4.5-5 million adults – 10 times more than those affected by Parkinson's disease. Starting with mild memory problems and ending with severe brain damage, Alzheimer's usually begins after the age of 60, the risk increasing with age. If no effective therapies are developed, by 2050 it is estimated that 13 million Americans will have the disease. In the United States, five percent of the population over age 65 and one-third of the population over age 85 are afflicted by it. It is the third most expensive disease to treat and is the third leading cause of death, trailing cancer and coronary heart disease.

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Besides LaFerla and Billings, other co-authors of the Neuron paper are Salvatore Oddo, Kim N. Green and James L. McGaugh – all researchers in the Department of Neurobiology and Behavior. The research was funded by grants from the National Institute on Aging and the Alzheimer's Association, as well as a National Research Service Awards postdoctoral fellowship.

About the University of California, Irvine: The University of California, Irvine is a top-ranked public university dedicated to research, scholarship and community service. Founded in 1965, UCI is among the fastest-growing University of California campuses, with more than 24,000 undergraduate and graduate students and about 1,400 faculty members. The second-largest employer in dynamic Orange County, UCI contributes an annual economic impact of $3 billion.