Potential drug target for Alzheimer’s identified

Researchers have identified an enzyme in the brain which presents a drug target to intervene in progression Alzheimer’s disease (AD) and other dementias. The researchers suggest that the enzyme, a serine/threonine kinase known as LIMK1, may play an important role in the degradation of dendritic spines, the connections between neurons in the brain. 

The team at the University of Alabama report the use of an experimental medication that appears to successfully inhibit LIMK1 and provide a level of protection for dendritic spines.

“This is the first study to showcase that inhibiting LIMK1 could provide a protective effect for dendritic spines,” said Dr Jeremy Herskowitz, assistant professor in the Department of Neurology, School of Medicine at the university. “In animal models, we’ve shown that increased activity of LIMK1 is linked to changes in the length and density of dendritic spines, which has implications for Alzheimer’s.”

In a healthy brain, LIMK1 regulates the size and density of dendritic spines. However, for patients with dementia, the enzyme is overactive and causes damage to the spines.

LIMK1 resides downstream of two other enzymes known to be associated with dementia. These Rho-associated kinases, known as ROCK 1 and ROCK 2, are increased in early Alzheimer’s disease. Investigators worldwide have looked to ROCK 1 and 2 as potential intervention targets in dementia.

“The ROCK kinases are proving to be challenging drug targets because inhibiting them may cause severe side effects, including a drop in blood pressure significant enough to cause death,” Herskowitz said. “But LIMK1, downstream in the signalling pathway, is regulated by the ROCK kinases, particularly ROCK 2. As far as we know now, inhibition of LIMK1 has no effect on ROCK and so it may not carry the same severe side effects.”

LIMK1 is also thought to play a role in cancer metastasis, so Herskowitz’s team turned to an experimental drug called SR7826, which is under development as a cancer therapeutic. SR7826 suppresses the activity of LIMK1. In an animal model, a single dose given once daily for 10 days raised dendritic spine density and increased the length of the spines.

“The drug had remarkable effects on the dendritic spines, results that we feel are significant and promising,” Herskowitz said. “This is one of the first scientific papers to suggest that LIMK1 might be a better target for intervention than the ROCK kinases.”

The findings were published in Science Signalling.