Alzheimer’s disease, a neurodegenerative disorder involving the deterioration of the brain’s nerve cells, is one of the most common forms of dementia – a generalized decline in memory, judgment, thinking, and learning ability. A progressive disease, Alzheimer’s can ultimately rob a person of capabilities or personality traits that have defined him or her for a lifetime, a consequence that’s often traumatic for family members, friends, and caregivers.

“The program for Alzheimer’s disease, and neurodegenerative diseases in general encompasses a wide variety of topics: genetic and/or proteomic markers, genetic susceptibility risk factors, gene/environment interactions in animal models, alterations in the processing or metabolism of specific proteins related to these diseases, and the identification of new targets so we can work on developing new therapies…”

Though discovered more than a century ago, Alzheimer’s remains a mysterious ailment. Researchers have discovered risk factors – such as head trauma, hypertension, or genetics – as well as brain abnormalities associated with Alzheimer’s: the accumulation of beta-amyloid protein plaques between neurons, and fibrous tangles of tau proteins within neural cells. But establishing a cause-effect relationship between these conditions and Alzheimer’s has proven elusive. As imaging technologies have matured to the point where amyloid plaques can be identified, for example, investigators have sometimes found the brains of patients with Alzheimer’s-like dementia to be free of amyloid plaques.

Because there remains no known cause nor cure, nor even a universally effective treatment for Alzheimer’s disease, the Department of Veterans Affairs’ (VA) Office of Research and Development (ORD) devotes considerable resources to investigating the basic mechanisms underlying the cause and progression of the disease. According to Dr. Lisa Opanashuk, scientific program manager for neurodegenerative disorders for ORD’s Biological Laboratory and Clinical Sciences R&D Services, more VA researchers are involved in studying Alzheimer’s than any other neurodegenerative disease. “The program for Alzheimer’s disease, and neurodegenerative diseases in general,” she said, “encompasses a wide variety of topics: genetic and/or proteomic markers, genetic susceptibility risk factors, gene/environment interactions in animal models, alterations in the processing or metabolism of specific proteins related to these diseases, and the identification of new targets so we can work on developing new therapies. We look at neuronal death, inflammation, oxidative stress, and free-radical injury in animal models of these neurodegenerative diseases, along with mitochondrial dysfunction and signaling factors.”

 

The Molecular Mysteries of Alzheimer’s

Some of the most extensive Alzheimer’s-related proteomic studies (investigations of the structures and functions of proteins) are being conducted at the laboratory of Tony Wyss-Coray, Ph.D., a professor of neurology and neurological sciences at the Stanford University School of Medicine and senior research career scientist at the Palo Alto Health Care System. Wyss-Coray and colleagues seek to understand more about how the proteins involved in cellular communications – a wide variety of compounds, generally known as cytokines – change in normal aging and in the neurodegenerative disease process. “We measure now more than 500 of these types of proteins,” he said. “When these factors change due to aging or disease, we hope to get information about the biological changes that occur in the organism.” Wyss-Coray’s laboratory measures the presence of these proteins both in mice that model either normal aging or Alzheimer’s disease, and also in human plasma samples taken from healthy aging individuals and people with early- or late-stage Alzheimer’s disease.

Normal aging, said Wyss-Coray, can change the levels of some of these proteins dramatically – by 50 percent, 100 percent, or more. The question then becomes, he said, whether these changes are simply part of normal aging, or involved some way in neurodegeneration. His laboratory’s approach toward investigating this question involves a method known as parabiosis: the surgical connection of two mice – one old, one young – at their flanks, creating a capillary network that interconnects their blood supplies.

“What we find is that the old brain gets basically rejuvenated,” said Wyss-Coray. “The old mouse makes more neural stem cells and increases production of neurons that are involved in learning and memory. It increases expression of many genes that are involved in memory formation. Synaptic density goes up, and synaptic plasticity in electrophysiological recordings is also improved.”