Newswise — Researchers at the University of Pennsylvania School of Medicine have shown that impaired function and loss of synapses in the hippocampus of a mouse form of Alzheimer's disease (AD) is related to the activation of immune cells called microglia, which cause inflammation. These events precede the formation of tangles " twisted fibers of tau protein that build up inside nerve cells " a hallmark of advanced AD. The researchers report their findings in the February 1 issue of Neuron.
"Abolishing the inflammation caused by the accumulation of the tau protein might be a new therapy for treating neurodegenerative disorders," says senior author Virginia Lee, PhD, Director of the Center for Neurodegenerative Disease Research. "This work points the way to a new class of drugs for these diseases." In addition, the immunosuppressant FK506 diminishes neuron loss and extends the life span of the transgenic Alzheimer's mice. Normally only 20 percent of these mice survive by one year. With FK506, 60 percent of the mice were alive by one year. Lee and colleagues developed their mouse model about four years ago, an improvement on their first tau mouse developed seven years ago. This model is unique in that it more closely mirrors human Alzheimer's because it shows more and consistent tangles in the hippocampus than other mouse models. In Alzheimer's and other neurodegenerative diseases, misfolded tau and other proteins accumulate inside neurons. Proteins used to make healthy synapses are moved via microtubules to the synapse along the nerve axon. However, accumulation of tau in clumps inside nerve cells (that is, the tangles described 100 years ago by Alzheimer in the first reported AD patient) impairs the function of nerve cells and causes them to degenerate. This is because tau is needed to stabilize microtubules like cross-ties stabilize train tracks. But if tau clumps, the microtubules break up, thereby disrupting the transportation network in normal nerve cells. This has lethal consequences because nerve-cell axons and dendrites are critically dependent on this normal transportation network. The misfolded tau proteins aggregate and form sheets called fibrils that accumulate in different parts of the brain. The resulting impaired axonal transport of proteins and other cargoes needed to maintain synapses can cause nerve-cell loss, with subsequent dementia, parkinsonism, or weakened motor skills in peripheral muscles, and later muscle atrophy. Hence, blocking fibril formation or eliminating misfolded proteins have become targets for drug discovery for Alzheimer's, Parkinson's, and related disorders. "The ultimate aim of this work is to develop diagnostics to detect earlier stages of Alzheimer's disease to optimize the possibility of treating patients and discovering new and more effective drugs before the brain is irreparably damaged and cognitive functions are lost," says Lee. Co-authors are Yasumasa Yoshiyama, Makoto Higuchi, Bin Zhang, and John Trojanowski, all from Penn, and Shu-Ming Hiang and Nobuhisa Iwata from RIKEN Brain Science Institute (Wako, Japan) and Jun Maeda and Tetsuya Suhara from the National Institute of Radiological Science (Chiba, Japan). The research was sponsored by the National Institute of Aging.
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