- Agomelatine improves the memory and learning of Alzheimer’s mice by enhancing autophagy — the cellular waste clearance system that deteriorates with age.
- Antidepressant drugs could potentially treat the cognitive deficits associated with Alzheimer’s disease.
None of us are safe from Alzheimer’s disease (AD), as 90% of cases are sporadic. For those already diagnosed, there is no good treatment that stops its progression. With cases expected to skyrocket in the coming years, the urgency of finding an appropriate treatment has brought scientists to explore the repurposing of existing drugs like antidepressants.
Li and colleagues from the Shanxi Medical University in China present evidence in Progress in Neurobiology that points to the antidepressant agomelatine as a potential treatment for the cognitive impairments associated with AD. They show that a protein that inhibits autophagy called Ubec2 is elevated in the brains of AD patients. This protein is also elevated in the brains of mice that model AD and can be suppressed by treatment with agomelatine. Furthermore, suppressing Ubec2 with agomelatine leads to the prevention of learning and memory deficits in AD mice.
Agomelatine Improves Cognition in Alzheimer’s Mice
The accumulation of a protein called amyloid in the brain is a hallmark of AD. Amyloid plaques are toxic to brain cells and lead to cognitive deficits. Li and colleagues observed these amyloid plaques in the brains of AD mice, confirming their likeness to AD patients. After treating the AD mice with the antidepressant agomelatine, the investigators saw a reduction in amyloid. Furthermore, they showed that agomelatine improved the learning and memory of the mice, suggesting that agomelatine prevents the cognitive deficits associated with AD mice by reducing brain amyloid.
Agomelatine is an antidepressant drug known to treat mood disorders and insomnia. It also reduces autophagy, a process that declines with aging. A lack of autophagy is associated with many age-related diseases. Li and colleagues showed that a protein called Ubec2, which inhibits autophagy, is elevated in the brains of AD mice and AD patients. They next showed that agomelatine suppressed the amyloid-mediated elevation of Ubec2c in microglia cells — the brain’s resident immune cells. Microglia cells are important for clearing unwanted cellular material such as amyloid plaques.
The Chinese researchers then reasoned that suppressing Ubec2c could lead to the clearance of amyloid and improve cognitive deficits. To test this, they virally delivered a molecule to the brains of Alzheimer’s mice to suppress Ubec2c. Indeed, reducing Ubec2c decreased amyloid and improved learning and memory. Together, these findings suggest that agomelatine could reduce amyloid by suppressing Ubec2c to promote autophagy.
Can Antidepressants Treat Cognitive Impairments?
By analyzing previous clinical trials, a recent study showed that the FDA-approved antidepressants imipramine and olanzapine could block the formation of amyloid and improve cognitive performance in AD patients. However, both these drugs have known interactions and side effects and are prescribed to the elderly cautiously. In a similar recent study that analyzed past clinical trials, it was found that noradrenergic drugs, a class of antidepressants, could also potentially treat cognitive impairments in AD patients. These drugs do not come without risk, as they could elevate heart rate and blood pressure.
The drug used by Li and colleagues, agomelatine, has outperformed many FDA-approved antidepressants but is not FDA-approved. However, it is approved in Europe and Australia under the names Valdoxan and Thymanax. The findings of Li and colleagues corroborate with other animal studies showing that antidepressants, namely SSRIs (selective serotonin reuptake inhibitors) reduce amyloid and improve learning and memory. Overall, the use of antidepressant medications to treat the cognitive impairments of AD seems promising.