Study Shows Agomelatine Prevents Cognitive Deficits in Alzheimer’s

Chinese scientists find that the antidepressant drug agomelatine reverses cognitive deficits in a mouse model for Alzheimer’s disease.

Key Points:

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.

(Li et al., 2022 | *Progress in Neurobiology*) **Agomelatine Prevents Cognitive Deficits in Alzheimer’s Mice.** Normal (WT) and AD mice (APP/PS1) were injected with either 10 mg/kg of agomelatine (AGO) or no agomelatine (Veh). They were trained to learn and remember the location of a platform in a specific quadrant of a pool of water as part of the Morris water maze test. More time spent in the correct quadrant represents improved learning and memory. The left graph shows that AGO increased the percentage of time in the correct/target quadrant in the APP/PSI mice. The images on the right show the path (red line) each group of mice took to get to the correct (upper-left) quadrant.

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.

(Li et al., 2022 | *Progress in Neurobiology*) **Promoting Autophagy by Suppressing Ubec2 Prevents Cognitive Deficits in Alzheimer’s mice.** To reduce Ubec2 and promote autophagy, a viral vector (AAV) was used to deliver a small RNA molecule (shRNA) that eliminates the protein expression of Ubec2 (shUbe2c). An shRNA that doesn’t eliminate Ubec2 (shRNA ctrl) was used as a control. The left graph shows that eliminating Ubec2 in AD mice (gray, APP/PS1-shUBec2c) increases the time spent in the correct quadrant during the Morris water maze test to the same level as normal mice (WT-shRNA ctrl). The right images show the path taken by each group of mice to the correct (upper-right) quadrant.

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.