A crucial new frontier in neuroscience is a better
understanding of how proteins such as PrP, amyloid beta, tau, and others
aggregate and spread, and kill brain cells. In this month’s Cerebrum article, “The Malignant Protein Puzzle,” two scientists who have collaborated
for 30 years to identify the pathogenesis of Alzheimer’s disease and comprehend
the role of abnormal proteins in neurodegeneration write about the latest
advances in an area that has the potential to make a difference in helping
people with dementia, Parkinson’s, CTE, ALS, and other neurodegenerative
disorders. One of the authors, Lary C. Walker, Ph.D., associate director of the Alzheimer’s Disease Research Center at Emory University, elaborates on their collaboration
and some of the science in their article.
What inspired you and
Mathias Jucker to work together?
I was at Johns Hopkins and Mathias was a fellow across town at
the National Institute on Aging. We had a common interest in the aging brain
and we met through seminars that took place in Baltimore. Through various
discussions, we developed a strong common interest in the underpinnings of
Alzheimer's disease, one that has taken us to this day with our collaborations.
Does the fact that you now
work in Atlanta and Dr. Jucker in Germany impact your collaboration?
It would have mattered 30 years ago,
but it's so much easier now to communicate. We converse mainly by email, and we
speak on the phone regularly. It's really not that different from having a
colleague on the other side of campus.
Can you explain in
simple terms what a prion is?
A prion is basically a form of a
normally produced protein that misfolds. In other words, the protein (called
the prion protein) folds into the wrong shape and, in that shape, has
completely different properties than the normal protein. Prions are able to
compel other prion protein molecules to misfold, which is the most important property
for disease. They also become sticky in this state, which causes them to bind
to one another. That's why, with prion disease (and many other neurodegenerative
diseases), you often see characteristic clumps of sticky, misfolded proteins in
What is the difference
between plaques and tangles?
Plaques and tangles are made of different proteins; plaques
are extracellular clumps of amyloid beta protein (Aβ), whereas the tangles consist
of intracellular assemblies of the tau protein. In both cases the proteins are
misfolded, in which state they aggregate into long polymers that, in large
numbers, constitute the plaques and tangles that we see under the microscope.
You write that “the
exact mechanisms by which nervous tissues are damaged in prion diseases remain
incompletely understood—and that poses a challenge for future research.” Can
you articulate this misunderstanding?
is true for all diseases that involve protein aggregation. Protein aggregation
is telling us that there is a disease process happening. But exactly which form
of the aggregated protein is causing cells to die remains uncertain at this
point. One of the things that has happened in the field in the last 15 years or
so is the realization that these lesions – deposits of protein we can see with
the light microscope – may just be a sign that the proteins are abnormal. The
actual toxic forms may, in fact, be much smaller, perhaps as few as two or
three molecules of amyloid beta or tau or prion protein bound together into
tiny assemblies called oligomers. Those oligomers can bind to membranes or to
transmitter receptors on neurons and disrupt the function of the cells. We
think that oligomers may be an important toxic form, but there is evidence that
different manifestations of aggregated proteins can, probably in different ways,
interfere with brain function. As one example, the relatively big clumps of
protein in plaques are linked to an inflammatory reaction in the surrounding
Why is it more likely
that malignant proteins seem to misfold and aggregate and cause dementias more
as people age?
That's the $64,000 question.
Aging is the major risk factor for virtually all of these diseases. We don't
know the reason for sure, but one possibility is that, as we age, the cellular
mechanisms that control the production and the disposal of proteins become
compromised. As a result, the cells are no longer able to get rid of abnormal proteins.
Because of this, the odds go up that misfolded proteins will persist and then
seed the continued aggregation of other protein molecules. Which disease develops
may depend, to some extent, on which particular misfolded protein happens to
gain a foothold in the brain first.
CTE (Chronic Traumatic Encephalopathy),
one of the diseases linked to malignant proteins, has so far only been
diagnosed in the brains of people who have died. Why is CTE so difficult to
detect in the brains of the living?
pathological feature of CTE is the accumulation of tau protein in neurofibrillary
tangles. In recent years, new imaging
agents have been developed that are able to detect tau protein in the brain. These
will be applied more and more to patients who are suspected of having CTE,
allowing physicians to determine, with reasonable certainty, that bona fide CTE
exists in the brain. Rapid strides are being made in the development of
selective agents that can detect various aggregated proteins in living patients.
Meanwhile, microscopic examination of brain tissue is still the definitive test
Beyond CTE, specific imaging agents are helping us also to understand
various aspects of Alzheimer's disease. There are now several sensitive ligands
that can detect Abeta protein levels in the central nervous system in order to facilitate
the diagnosis of Alzheimer's disease. In addition, tests that measure the
levels of Abeta and tau in spinal fluid are helpful for diagnosis. The ideal biomarker, though, would be one
that doesn’t require radiation or a spinal tap; we are not there yet, but many
talented researchers are seeking better ways to diagnose CTE, Alzheimer’s, and
other neurodegenerative diseases.
TIME magazine recently featured “The
Alzheimer’s Pill” on its cover in a series of articles on longevity.
Essentially, it talks about LM11A-31, a drug developed by Dr. Frank Longo at
Stanford and now in the human clinical trial phase. What do you think about its
I am skeptical of any
claim that a pill will prevent or cure Alzheimer's disease, and this is no
exception. One of the problems with Alzheimer's disease (and this is probably
true of most chronic neurodegenerative diseases) is that it develops in the
brain over a long, drawn out period. We now know that that the aggregation of
proteins in the Alzheimer’s brain begins as much as 20 years or more before the
patient shows up in the doctor’s office and says, ‘ I'm not remembering so well.’
Many in the field now recognize the need to stop this process very early on—long
before signs of dementia first appear. And that's going to require nipping the proteopathic
cascade in the bud. Although there are
many promising drugs and drug leads, not one has come along yet that has been
shown to actually slow or reverse this process.
Developing new drugs to
destroy malignant proteins represents the next frontier for neuroscience.
Besides the difficulty in conducting clinical trials because of such obstacles
as long lead time and large control groups, why, from a research standpoint,
has this proved so difficult?
we have a validated biomarker of disease progression, any trial that is going
to show a significant, disease-modifying effect on Alzheimer's disease must play
out over a fairly long period of time. Such long-term trials are risky and
expensive. It's not like an infection, where we can give an antibiotic and then
see a response within 24 hours. If it’s
true that we need to intervene early in order to prevent or delay the onset of
Alzheimer's, then we’re talking about a decade-long trial in some instances. So
from a drug development standpoint, it's still a challenge to determine whether
a given intervention will actually change the course of the disease.
this regard, there are clinical trials in progress where the idea is to study
people with genetic mutations that will, without doubt, cause them to develop
Alzheimer's disease as they get older. The researchers know from the subjects’
family histories the approximate age when the signs of dementia will appear. By
treating at-risk people in these families with potential therapeutic agents well
before the onset of dementia, it is hoped that the onset of the disease will be
delayed. We should know within the next few years whether early intervention is
successful in these cases. I am hopeful.
You write that John
Griffith once prophetically described how “a protein-only agent might multiply
using the host’s genetic machinery to generate more protein.”
Many of our
articles talk about genetics as our best chance to defeat various
neurobiological disorders. A few months ago a group of scientists meeting in
Washington called for a moratorium on making inheritable changes to the human
genome. What are your thoughts on tinkering with the DNA of embryos to reduce
the risk of mental disorders such as Alzheimer’s?
There is no question that the use of our knowledge of
genetics to reduce human suffering is a worthwhile goal. CRISPR/Cas9 and
related technologies have made the direct manipulation of genes much simpler. The
problem is that we just don't know enough about potential off-target effects of
such gene manipulation to determine whether an intervention that prevents disease
might inadvertently interfere with the function of other genes. Then there's also the possibility that this technology might be used just to change certain common traits in the
offspring—make someone taller or give them blue eyes, for example. Who will
decide how this technology will be used? It’s a proverbial slippery slope with
significant implications for society.