(PHILADELPHIA) – 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
which cause inflammation. These events precede the formation of
– 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.
Microglial activation in the central
nervous system of transgenic tau mice.
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“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
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
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,
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 Huang 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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