UNTANGLING TREATMENTS FOR ALZHEIMER'S DISEASE: TARGETING TAU AS A THERAPY
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NR-11-05 (11/13/05). For more information, please contact Sara Harris at (202) 462-6688 or sharris@sfn.org.
UNTANGLING TREATMENTS FOR ALZHEIMER'S DISEASE: TARGETING TAU AS A THERAPY
WASHINGTON, DC, November 13, 2005 — New studies shed light on the role of the protein tau in Alzheimer's disease and other neurodegenerative diseases, and on its possible use as a target for therapy.
Scientists are determining how tau misfolds and clumps to form neurofibrillary tangles, which are a characteristic feature found in the brains of Alzheimer's disease patients. Other work shows that early changes in tau that precede the formation of the tangle are tied to early Alzheimer's disease symptoms and that a vaccine may be effective against tau’s ill effects in early Alzheimer's disease. Scientists also report that findings from other neurodegenerative diseases such as Parkinson’s disease can help advance research on Alzheimer's disease.
“These studies open the door for the development of therapies that target the pathological processing of tau as a treatment for Alzheimer’s disease,” says Gail V.W. Johnson, PhD, of the University of Alabama at Birmingham department of psychiatry. “If we can elucidate the early stages of tau malfunction, perhaps we can slow down Alzheimer's disease progression by targeting these processes.” Johnson is the chair of a symposium on “Tau: The Process of Tangle Formation and Its Effect on Neuronal Survival.”
Alzheimer's disease is the most common neurodegenerative disease among the elderly, affecting more than 4 million people in the United States. Estimates are that as many as 20 million people may develop Alzheimer's disease by mid-century. Symptoms of Alzheimer's disease include memory loss, especially for recent events during the disease’s early stages, and loss of the ability to think logically and clearly. Eventually, Alzheimer's disease patients are unable to do simple tasks such as maintaining personal hygiene.
One of the hallmark neuropathological characteristics of Alzheimer's disease is neurofibrillary tangles, which are primarily made up of the protein tau. Tau is a natural component of nerve cells that helps to regulate the movement of nutrient cargoes along microtubule tracks. In Alzheimer’s disease, events occur that result in tau’s being abnormally modified, which impairs the protein’s ability to bind to microtubules and help move essential nutrients through nerve cells. Instead, tau binds to itself, resulting in the classic neurofibrillary tangles of Alzheimer’s disease.
New work is showing that tau can exert its toxic effects even before tangles form. “Abnormal levels or processing of tau can actually perturb cell functions very early on, and could explain some of the early signs of Alzheimer’s disease,” says Eva-Maria Mandelkow, MD, PhD, of the Max Planck Unit for Structural Molecular Biology in Hamburg, Germany.
Mandelkow and her colleagues imaged live cells to study the movement of nutrients along microtubule tracks. So-called motor proteins move along the tracks to help move the nutrients. Mandelkow’s group observed that tau can inhibit these movements, leading to traffic jams within the nerve cell’s extensions, or axons, that damage neurons. Bearing the brunt of the damage are synapses—the critical juncture where information can transfer from one neuron to another.
“Traffic jams in neurons caused by early defects in tau protein could contribute to the loss of synapses and the memory loss observed in early Alzheimer’s disease,” Mandelkow says.
Alzheimer's disease is marked not only by neurofibrillary tangles containing misformed tau, but also by lesions called amyloid plaques that develop outside nerve cells and contain amyloid beta peptide. These two types of lesions interact to produce Alzheimer’s disease symptoms. Recognizing this, Frank M. LaFerla, PhD, of the University of California, Irvine, department of neurobiology and behavior, recently developed mice with mutations in genes that result in the formation of both amyloid plaques and neurofibrillary tangles.
LaFerla's laboratory developed a mouse model of Alzheimer's disease containing three mutant human genes—amyloid precursor protein (APP), presenilin-1 (PS1), and tau. Mutations in APP and PS1 can increase the production of amyloid beta and harm the body's ability to clear amyloid beta, allowing it to accumulate both inside and outside nerve cells and interfere with nerve impulses. Mutations in tau have been shown to cause a rare form of dementia characterized by loss of nerve cells and the presence of neurofibrillary tangles similar to those in Alzheimer's disease.
The mice containing the mutant human genes developed malfunctions in amyloid beta and tau in a way that mimics what happens in the human Alzheimer's disease brain. The researchers could now test how well anti-Alzheimer's disease therapies work on reducing the effects of both amyloid beta-containing plaques and tau-containing neurofibrillary tangles.
LaFerla and his colleagues found that vaccinating the mice with amyloid beta in the early stages of the disease process not only reduced the amount of amyloid beta in their brains, but also the early tau formations. However, the amyloid beta vaccine did not reduce the more mature neurofibrillary tangles that develop later in the disease.
“The findings in these mice appear to agree with data from Alzheimer’s disease patients who received amyloid beta immunotherapy,” says LaFerla. “These findings suggest that concomitantly treating both plaques and tangles may provide the most effective means for treating Alzheimer's disease patients.”
In other work, scientists are exploring similarities between Alzheimer's disease and other neurodegenerative diseases to find clues to how Alzheimer’s disease might develop. In Alzheimer's disease, Parkinson's disease, and other aging-related neurodegenerative disorders, proteins misfold and accumulate as “trash” in the brain. While tau-containing neurofibrillary tangles develop in Alzheimer's disease, alpha-synuclein accumulates as structures known as Lewy bodies in the brains of Parkinson's disease patients.
“Because Alzheimer's disease patients often develop Parkinson’s disease and vice versa and because similar misfolded proteins accumulate in both disorders, the diseases may be linked by a common mechanism,” says Virginia M.-Y. Lee, PhD, of the Center for Neurodegenerative Disease Research at the University of Pennsylvania School of Medicine in Philadelphia.
Studies from Lee’s lab show that alpha-synuclein and tau can synergize each others’ clumping—alpha-synuclein could initiate or facilitate tau tangle formation in Alzheimer's disease. Indeed, clumps containing alpha-synuclein are often present in the brains of Alzheimer’s disease patients, as well as in Parkinson’s disease patients. “Although we don’t know exactly how neurofibrillary tangles and Lewy bodies can lead to brain degeneration in Alzheimer’s disease and Parkinson’s disease, the two disorders are a prime example of how research in one area can have a positive influence on others,” Lee says.
