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 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.
Source: https://einsteinmed.org/news/2563/experimental-drug-shows-potential-against-alzheimers-disease/
Source: Experimental
drug shows potential against Alzheimer’s disease – Scents of Science
(myfusimotors.com)
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