Targeting Tau: Inflammation Study
Suggests New Approach for Fighting Alzheimer’s
(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 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
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
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,”
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
PENN Medicine is a $2.9 billion enterprise dedicated
to the related missions of medical education, biomedical research, and
high-quality patient care. PENN Medicine consists of the University of
Pennsylvania School of Medicine (founded in 1765 as the nation's first
medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #3 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System includes three hospitals, all of which have received numerous national patient-care honors [Hospital of the University of Pennsylvania; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center]; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.