"Untangling" Tau: New Mouse Model Shows Key Feature Of Alzheimer's Disease

In the study, scientists inserted human tau genes into mice which later developed masses of abnormal tau filaments in nerve cells within the spinal cord, cortex and brainstem, three critical regions of the central nervous system. As the mice aged, insoluble masses of tau filaments grew in number. The animals also showed evidence of nerve cell degeneration and impaired movement, unlike their littermates lacking the inserted tau gene. The strain was created under the direction of Virginia M-Y. Lee, Ph.D., M.B.A., and John Q. Trojanowski, M.D., Ph.D. at the University of Pennsylvania's Center for Neurodegenerative Disease Research in Philadelphia.

The mice do not completely model AD, but they more closely resemble other human brain diseases that accumulate AD-like tau deposits in regions deep within the central nervous system, Dr. Lee is careful to point out.

"We know that tau-containing tangles are an important feature of Alzheimer's disease, but we're not sure about how it fits into the development and progression of the disease, so the tau mouse model is very important," says Dr. D. Stephen Snyder, who directs studies of the Etiology of Alzheimer's Disease at NIA's Neuroscience and Neuropsychology of Aging Program. "It should help us look at normal and abnormal tau function, for example, to study and measure the accumulation of tau and to determine how the known mutations lead to the death of neurons. Less clear is whether tau will eventually prove to be a useful diagnostic marker for the tauopathies and, importantly, for AD."

The two neuropathlogical hallmarks of Alzheimer's disease are senile plaques, which are made of a protein fragment called beta amyloid, and neurofibrillary tangles, which are made of abnormal twisted strands of the protein, tau. Tau formation is related to the severity of disease; the more advanced the stage of disease, the more tau deposits in the brain. Animal models already exist for other features of Alzheimer's disease, including strains bred with mutated forms of the human amyloid precursor protein, which causes amyloid to form, and mice bred with the presenilin and apoE4 genes, also implicated in Alzheimer's disease.

Dementia refers to a loss of memory and reasoning and specifically to a progressive deterioration that is severe enough to prevent normal functioning. AD is the most common cause of dementia among people age 65 and older. AD affects as many as 4 million Americans in the United States. The prevalence of AD doubles every 5 years beyond age 65. Some studies indicate that nearly half of all people age 85 and older have symptoms of AD.

Researchers use the term "tauopathy" to describe a grouping of dementing diseases in which tau is implicated, such as a unique form of dementia which involves several mutations in the tau gene affecting over twenty distinct families. They also include Pick's disease and progressive supranuclear palsy (PSP), which are not caused by tau genetic mutations. Tauopathies differ from AD in a number of important ways. Clinical signs associated with tauopathies vary widely and range from schizophrenia and Parkinsonian-like tremors to language and behavioral disturbances. In addition, people with tauopathies may have abundant AD-like deposits of tau filaments, but they may not have deposits of beta amyloid. Masses of tau filaments accumulate in different brain regions from those affected by AD and the tau filaments themselves often have a slightly different structure from those in AD. And because memory loss in some tauopathies is similar to that experienced by patients with AD, the prevalence of tauopathies - distinct from AD - remains uncertain.

Scientists do not yet know how tau and amyloid deposits form, or how they cause cells to die in AD. The two may form independently of one another, or one before the other. Scientists are also working to understand how the two produce disease in the brain, and to understand why and how tau deposits accumulate. But they know that the protein is critical to cell survival and helps maintain the cell's internal support structure or cytoskeleton.

The NIA is the lead federal agency supporting and conducting Alzheimer's disease research, including studies of the basic, clinical, and epidemiological aspects of this and other related dementias of aging. The NIA's Alzheimer's Disease Education and Referral (ADEAR) Center can provide more information on Alzheimer's disease by calling 1-800-438-4380 or visiting the ADEAR Web site at http://www.alzheimers.org.