Removing 'garbage' from brain cells improves memory in mice
From:
Albert Einstein College of Medicine
April 22, 2021 -- The drug works by
reinvigorating a cellular cleaning mechanism that gets rid of unwanted proteins
by digesting and recycling them. The
study was published online today in the journal Cell.
"Discoveries in mice don't always
translate to humans, especially in Alzheimer's disease," said co-study
leader Ana Maria Cuervo, M.D., Ph.D., the Robert and Renée Belfer Chair for the
Study of Neurodegenerative Diseases, professor of developmental and molecular
biology, and co-director of the Institute for Aging Research at Einstein.
"But we were encouraged to find in our study that the drop-off in cellular
cleaning that contributes to Alzheimer's in mice also occurs in people with the
disease, suggesting that our drug may also work in humans." In the 1990s,
Dr. Cuervo discovered the existence of this cell-cleaning process, known as
chaperone-mediated autophagy (CMA) and has published 200 papers on its role in
health and disease.
CMA becomes less efficient as people
age, increasing the risk that unwanted proteins will accumulate into insoluble
clumps that damage cells. In fact, Alzheimer's and all other neurodegenerative
diseases are characterized by the presence of toxic protein aggregates in
patients' brains. The Cell paper reveals a dynamic interplay
between CMA and Alzheimer's disease, with loss of CMA in neurons contributing
to Alzheimer's and vice versa. The findings suggest that drugs for revving up
CMA may offer hope for treating neurodegenerative diseases.
Establishing CMA's Link to Alzheimer's
Dr. Cuervo's team first looked at
whether impaired CMA contributes to Alzheimer's. To do so, they genetically
engineered a mouse to have excitatory brain neurons that lacked CMA. The
absence of CMA in one type of brain cell was enough to cause short-term memory
loss, impaired walking, and other problems often found in rodent models of
Alzheimer's disease. In addition, the absence of CMA profoundly disrupted
proteostasis -- the cells' ability to regulate the proteins they contain.
Normally soluble proteins had shifted to being insoluble and at risk for
clumping into toxic aggregates.
Dr. Cuervo suspected the converse was
also true: that early Alzheimer's impairs CMA. So she and her colleagues
studied a mouse model of early Alzheimer's in which brain neurons were made to
produce defective copies of the protein tau. Evidence indicates that abnormal
copies of tau clump together to form neurofibrillary tangles that contribute to
Alzheimer's. The research team focused on CMA activity within neurons of the
hippocampus -- the brain region crucial for memory and learning. They found
that CMA activity in those neurons was significantly reduced compared to
control animals.
What about early Alzheimer's in people
-- does it block CMA too? To find out, the researchers looked at single-cell RNA-sequencing
data from neurons obtained postmortem from the brains of Alzheimer's patients
and from a comparison group of healthy individuals. The sequencing data
revealed CMA's activity level in patients' brain tissue. Sure enough, CMA
activity was somewhat inhibited in people who had been in the early stages of
Alzheimer's, followed by much greater CMA inhibition in the brains of people
with advanced Alzheimer's.
"By the time people reach the age
of 70 or 80, CMA activity has usually decreased by about 30% compared to when
they were younger," said Dr. Cuervo. "Most peoples' brains can
compensate for this decline. But if you add neurodegenerative disease to the
mix, the effect on the normal protein makeup of brain neurons can be
devastating. Our study shows that CMA deficiency interacts synergistically with
Alzheimer's pathology to greatly accelerate disease progression."
A New Drug Cleans Neurons and Reverses
Symptoms
In an encouraging finding, Dr. Cuervo
and her team developed a novel drug that shows potential for treating
Alzheimer's. "We know that CMA is capable of digesting defective tau and
other proteins," said Dr. Cuervo. "But the sheer amount of defective
protein in Alzheimer's and other neurodegenerative diseases overwhelms CMA and essentially
cripples it. Our drug revitalizes CMA efficiency by boosting levels of a key
CMA component."
In CMA, proteins called chaperones bind
to damaged or defective proteins in cells of the body. The chaperones ferry
their cargo to the cells' lysosomes -- membrane-bound organelles filled with
enzymes, which digest and recycle waste material. To successfully get their
cargo into lysosomes, however, chaperones must first "dock" the
material onto a protein receptor called LAMP2A that sprouts from the membranes of
lysosomes. The more LAMP2A receptors on lysosomes, the greater the level of CMA
activity possible. The new drug, called CA, works by increasing the number of
those LAMP2A receptors.
"You produce the same amount of
LAMP2A receptors throughout life," said Dr. Cuervo. "But those
receptors deteriorate more quickly as you age, so older people tend to have
less of them available for delivering unwanted proteins into lysosomes. CA
restores LAMP2A to youthful levels, enabling CMA to get rid of tau and other
defective proteins so they can't form those toxic protein clumps." (Also
this month, Dr. Cuervo's team reported in Nature Communications that,
for the first time, they had isolated lysosomes from the brains of Alzheimer's
disease patients and observed that reduction in the number of LAMP2 receptors
causes loss of CMA in humans, just as it does in animal models of Alzheimer's.)
The researchers tested CA in two
different mouse models of Alzheimer's disease. In both disease mouse models,
oral doses of CA administered over 4 to 6 months led to improvements in memory,
depression, and anxiety that made the treated animals resemble or closely
resemble healthy, control mice. Walking ability significantly improved in the
animal model in which it was a problem. And in brain neurons of both animal
models, the drug significantly reduced levels of tau protein and protein clumps
compared with untreated animals.
"Importantly, animals in both
models were already showing symptoms of disease, and their neurons were clogged
with toxic proteins before the drugs were administered," said Dr. Cuervo.
"This means that the drug may help preserve neuron function even in the
later stages of disease. We were also very excited that the drug significantly
reduced gliosis -- the inflammation and scarring of cells surrounding brain
neurons. Gliosis is associated with toxic proteins and is known to play a major
role in perpetuating and worsening neurodegenerative diseases."
Treatment with CA did not appear to harm
other organs even when given daily for extended periods of time. The drug was
designed by Evripidis Gavathiotis, Ph.D.,, professor of biochemistry and of
medicine and a co-leader of the study.
Drs. Cuervo and Gavathiotis have teamed
up with Life Biosciences of Boston, Mass., to found Selphagy Therapeutics,
which is currently developing CA and related compounds for treating Alzheimer's
and other neurodegenerative diseases.
The study is titled,
"Chaperone-mediated autophagy prevents collapse of the neuronal metastable
proteome." The study's other co-leader and first author is Mathieu
Bourdenx, Ph.D., a postdoctoral fellow in Dr. Cuervo's lab and also a junior
researcher at the Institute of Neurodegenerative Diseases, University of
Bordeaux, France. Additional Einstein authors include: Adrián Martín-Segura,
Aurora Scrivo, Susmita Kaushik, Ph.D., Inmaculada Tasset, Ph.D., Antonio Diaz
and Yves R. Juste.
Other contributors include: Jose A.
Rodriguez-Navarro (formerly at Einstein) at Hospital Universitario Ramón y
Cajal, Madrid, Spain, Nadia J. Storm (formerly at Einstein) at University of
Copenhagen, Denmark, Qisheng Xin (formerly at Einstein), Erica Stevenson, Nevan
Krogan and Danielle L. Swaney both at University of California at San
Francisco, CA, Enrique Luengo at Universidad Autonoma de Madrid, Madrid, Spain,
Cristina Clement, Ph.D., and Laura Santambrogio, M.D., Ph.D., both at Weill
Cornell Medicine, New York, NY, Se Joon Choi, Ph.D., Eugene V. Mosharov and
David Sulzer, Ph.D., all at Columbia University Medical Center, New York, NY
and Fiona Grueninger, Ph.D., and Ludovic Collin both at Roche Pharma,
Switzerland.
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