Researchers at Albert Einstein College of Medicine have designed an
experimental drug that reversed key symptoms of Alzheimer's disease in mice.
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."
Reference:
Mathieu Bourdenx, Adrián MartÃn-Segura, Aurora Scrivo, Jose A.
Rodriguez-Navarro, Susmita Kaushik, Inmaculada Tasset, Antonio Diaz, Nadia
J. Storm, Qisheng Xin, Yves R. Juste, Erica Stevenson, Enrique Luengo,
Cristina C. Clement, Se Joon Choi, Nevan J. Krogan, Eugene V. Mosharov,
Laura Santambrogio, Fiona Grueninger, Ludovic Collin, Danielle L. Swaney,
David Sulzer, Evripidis Gavathiotis, Ana Maria Cuervo. Chaperone-mediated
autophagy prevents collapse of the neuronal metastable proteome. Cell, 2021;
DOI:
10.1016/j.cell.2021.03.048