"We show a gradual decrease in the activity of a form of cellular cleaning, known as chaperone-mediated autophagy (CMA), in the neurons of mouse models of dementia and in the brain of Alzheimer's disease patients," Dr. Ana Maria Cuervo of Albert Einstein College of Medicine in New York City told Reuters Health.
"We then report the development of an experimental drug (a CMA activator, or CA) that stimulates CMA in two different mouse models of dementia and reduces pathology and disease progression," she said by email.
"We were struck by the level of reduction of toxic protein that we observed after only three months of daily treatment," she noted, "in part because in one of the models the drug was administered late, when symptoms and pathology had already manifested."
"The work demonstrates the efficacy of a new intervention that reactivates in diseased cells a mechanism that is present in all healthy cells to protect against toxic proteins," she said.
As reported in Cell, Dr. Cuervo and colleagues first conducted a series of experiments in two Alzheimer mouse models. The first was genetically engineered to block neuronal CMA. This led to impaired neuronal function and disruptions in proteostasis - the cells' ability to regulate the proteins they contain - such that normally soluble proteins became insoluble and risked clumping into toxic aggregates. These changes are "all reminiscent of brain aging," the authors state in their paper. In addition, affected mice had impaired walking and other problems often found in mouse models of Alzheimer's disease.
Next, the team studied a model of early Alzheimer's in which neurons were induced to make defective copies of the tau protein, implicated in the neurofibrillary tangles that contribute to Alzheimer's in humans. They found significantly reduced CMA activity in hippocampal neurons - i.e., those involved in memory and learning.
They followed these experiments with investigations of single-cell RNA sequencing data from neurons obtained from postmortem brains of Alzheimer's patients and controls, and found that CMA activity was somewhat reduced in those with early-stage Alzheimer's, but significantly reduced in those who had advanced disease.
The researchers then gave the mice oral doses of CA over four to six months. This led to improvements in memory, mood, anxiety and walking ability, such that the treated mice more closely resembled healthy control mice. Further, CA administration significantly reduced levels of tau and protein clumps compared with untreated animals.
Study coauthor Dr. Evripidis Gavathiotis, also of Albert Einstein, said by email, "Our next step is to translate this therapeutic strategy to patients and identify a CA drug that can be safely applied to humans."
"Fortunately," he told Reuters Health, "the current CA drug is administered orally, has very good brain-blood barrier permeability and does not display toxic effects upon daily administration to mice for six months which, considering the 2.5 years life-span of mice, would equal more than 15 years of daily treatment in people."
"The CA drug will also be tested in larger animals and if no toxicity is detected, it will progress to human clinical trials for age-related diseases," he said. "Overall, based on experience with other drugs, CA will still require five to seven years until it can be administered to patients."
Dr. Howard Fillit, Founding Executive Director and Chief Science Officer of the Alzheimer's Drug Discovery Foundation in New York City, commented on the study in an email to Reuters Health. "The experiments and manipulations described in this study not only demonstrate the importance of this particular mechanism (CMA) for removing misfolded proteins," he said, "but also that this approach is druggable and amenable to drug development."
"We cannot conclude for certain whether or not these mechanisms apply in humans with neurodegeneration until therapeutic success is demonstrated," he noted. "However, this work does describe the presence of the failure of CMA in human brains of Alzheimer's patients from autopsy."
"This work is still in the pre-clinical phases, but the potential for this approach to be transformative for patients is possible in the relatively near future (five to 10 years)," Dr. Fillit concluded.
SOURCE: https://bit.ly/3txD5hg Cell, online April 22, 2021.
By Marilynn Larkin
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