Society for Neuroscience: Tau as a Target for Alzheimer’s Disease
Speakers: Gail V. W. Johnson, PhD, University of Alabama; Eva-Maria Mandelkow, MD, PhD, Max Planck, Germany; Frank M. LaFerla, PhD, Department of Neurobiology and Behavior; University of California, Irvine; and Virginia M.-Y. Lee, PhD, Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvania
New studies are elucidating the role of the protein tau in Alzheimer’s disease (AD) and other neurodegenerative diseases and 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 patients with AD. Other work shows that early changes in tau that precede the formation of the tangle are tied to early AD symptoms and that a vaccine may be effective against tau’s ill effects in patients with early AD.
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Scientists also report that findings from other neuro-degenerative diseases such as Parkinson’s disease (PD) can help advance research on AD. They hope that these studies will lead to the development of therapies that target the pathological processing of tau as a treatment for AD. They anticipate that if they can better understand the early stages of tau malfunction, then perhaps they will be able to delay AD progression.
One of the hallmark neuropathological characteristics of AD is neurofibrillary tangles. These tangles are composed primarily of tau, a natural component of nerve cells that helps to regulate the movement of nutrients along the microtubule tracks. In patients with AD, tau becomes abnormally modified; this impairs the protein’s ability to bind to microtubules and to move essential nutrients through nerve cells. Instead, tau binds to itself, resulting in the classic tangles.
It has now been observed that tau can exert its toxic effects even before tangles form. AD is marked not only by these tangles, which contain misformed tau, but also by lesions called amyloid plaques. These plaques develop outside the nerve cells and contain amyloid beta peptide. These two types of lesions interact to produce the symptoms of AD.
Recognizing these events, Frank M. LaFerla, PhD, developed mice with mutations in genes that caused the formation of both amyloid plaques and neurofibrillary tangles. His mouse model of AD contained three mutant human genes: (1) amyloid precursor protein (APP), (2) presenilin-1 (PS1), and (3) tau. canada drugs online
Mutations in APP and PS1 can increase the production of amyloid beta and harm the body’s ability to clear it, allowing it to accumulate inside and outside nerve cells and to interfere with nerve impulses. Tau mutations cause a rare form of dementia characterized by the loss of nerve cells and the presence of neurofibrillary tangles similar to those in AD.
The mice with the mutant human genes developed malfunctions in amyloid beta and tau in a way that mimics what happens in the brains of human beings with AD. The researchers were then able to test the ability of anti-AD therapies to reduce the effects of amyloid beta-containing plaques and tau-containing neurofibrillary tangles.
The LaFerla team found that vaccinating the mice with amyloid beta in early-stage disease reduced not only the amount of amyloid beta in their brains but also the quantity of 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 Dr. LaFerla. “These findings suggest that concomitantly treating both plaques and tangles may provide the most effective means for treating Alzheimer’s disease patients.” buy antibiotics no prescription
Scientists are also exploring similarities between AD and other neurodegenerative diseases and are looking for clues as to how AD might develop. With AD, PD, and other age-related neurodegenerative disorders, proteins misfold and accumulate as “trash” in the brain. While tau-containing neurofibrillary tangles develop in AD, alpha-synuclein accumulates as structures (called Lewy bodies) in the brains of patients with PD.
“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.
Studies from Dr. Lee’s laboratory show that alpha-synuclein and tau can synergize each other’s clumping: that is, alpha-synuclein may initiate or facilitate tau tangle formation in AD. Indeed, clumps containing alpha-synuclein are often present in the brains of both AD and PD patients.
