Scientists have discovered a “Big Bang” of Alzheimer’s disease – the
precise point at which a healthy protein becomes toxic but has not yet formed
deadly tangles in the brain.
A study from UT Southwestern’s O’Donnell Brain Institute provides novel
insight into the shape-shifting nature of a tau molecule just before it begins
sticking to itself to form larger aggregates. The revelation offers a new
strategy to detect the devastating disease before it takes hold and has spawned
an effort to develop treatments that stabilize tau proteins before they shift
shape.
“This is perhaps the biggest finding we have made to date, though it will
likely be some time before any benefits materialize in the clinic. This changes
much of how we think about the problem,” said Dr. Marc Diamond, Director for UT
Southwestern’s Center for Alzheimer’s and Neurodegenerative Diseases and a
leading dementia expert credited with determining that tau acts like a prion –
an infectious protein that can self-replicate.
The study published in eLife contradicts
the previous belief that an isolated tau protein has no distinct shape and is
only harmful after it begins to assemble with other tau proteins to form the
distinct tangles seen in the brains of Alzheimer’s patients.
Scientists made the discovery after extracting tau proteins from human
brains and isolating them as single molecules. They found that the harmful form
of tau exposes a part of itself that is normally folded inside. This exposed
portion causes it to stick to other tau proteins, enabling the formation of tangles
that kill neurons.
“We think of this as the ‘Big Bang’ of tau pathology,” said Dr. Diamond,
referring to the prevailing scientific theory about the formation of the
universe. “This is a way of peering to the very beginning of the disease
process. It moves us backward to a very discreet point where we see the
appearance of the first molecular change that leads to neurodegeneration in
Alzheimer’s. This work relied on a close collaboration with my colleague, Dr.
Lukasz Joachimiak.”
Despite billions of dollars spent on clinical trials through the decades,
Alzheimer’s disease remains one of the most devastating and baffling diseases
in the world, affecting more than 5 million Americans alone.
Dr. Diamond is hopeful the scientific field has turned a corner, noting
that identifying the genesis of the disease provides scientists a vital target
in diagnosing the condition at its earliest stage, before the symptoms of
memory loss and cognitive decline become apparent.
His team’s next steps are to develop a simple clinical test that examines a
patient’s blood or spinal fluid to detect the first biological signs of the
abnormal tau protein. But just as important, Dr. Diamond said, efforts are
underway to develop a treatment that would make the diagnosis actionable.
He cites a compelling reason for cautious optimism: Tafamidis, a recently
approved drug, stabilizes a different shape-shifting protein called
transthyretin that causes deadly protein accumulation in the heart, similar to
how tau overwhelms the brain.
“The hunt is on to build on this finding and make a treatment that blocks
the neurodegeneration process where it begins,” Dr. Diamond said. “If it works,
the incidence of Alzheimer’s disease could be substantially reduced. That would
be amazing.”
Dr. Diamond’s lab, at the forefront of many notable findings relating to
tau, previously determined that tau acts like a prion – an infectious protein
that can spread like a virus through the brain. The lab has determined that tau
protein in the human brain can form many distinct strains, or self-replicating
structures, and developed methods to reproduce them in the laboratory. He said
his newest research indicates that a single pathological form of tau protein
may have multiple possible shapes, each associated with a different form of
dementia.
