Healthy dendritic spines
Inhibiting an enzyme called LIMK1 seems to improve the length and density of dendritic spines, shown here in green. Healthy dendritic spines are thought to have a protective effect against Alzheimer's disease. [UAB]

An enzyme that is the target for experimental anticancer drugs may also represent a novel target for Alzheimer’s disease (AD), according to scientists at the University of Alabama at Birmingham (UAB) School of Medicine. Their in vitro experiments and studies in mice found that inhibiting the serine/threonine kinase LIMK1 (LIM domain kinase isoform 1) protects nerve cell dendritic spines, the progressive loss of which is linked with cognitive decline in neurodegenerative disorders such as AD.

“In this study, we were able to provide a protective effect to the dendritic spines by means of an experimental drug that inhibited activity of LIMK1,” said Jeremy Herskowitz, PhD, an assistant professor in the department of neurology, School of Medicine at UAB. “The drug had remarkable effects on the dendritic spines, results that we feel are significant and promising. We observed no negative side effects.”

The researchers reported their findings in Science Signalling, in a paper titled, “Pharmacologic inhibition of LIMK1 provides dendritic spine resilience against β-amyloid.”

AD is characterized by the accumulation of β-amyloid (Aβ) deposits that form into plaques, and the development of neurofibrillary tangles (tau tangles) in the brain. Cognitive decline in AD results from the loss of synapses—the junctions between individual neurons—in regions of the brain that are critical for memory processes. Dendritic spines are nerve cell projections that act as the bridges connecting one neuron to another via the synapses, and previous research has shown that it may be synaptic loss and dendritic spine damage that are more closely linked with cognitive decline than are the Aβ deposits themselves. “Synapse or dendritic spine loss correlates more strongly with cognitive impairment in AD than β-amyloid (Aβ) or neurofibrillary tangle pathology, yet few therapeutic strategies target spines or synapse,” the authors wrote.

Previous work in the Herskowitz lab had shown that individuals with longer, more numerous dendritic spines didn’t develop dementia, even if they had tell-tale amyloid plaques and tau tangles. Dendritic spine integrity seemed to be regulated by the enzyme LIMK1, which is upregulated in AD. “In a healthy brain, LIMK1 appears to regulate the size and density of dendritic spines,” Herskowitz said. “In dementia, the enzyme is overactive, leading to damage to the spines.”

LIMK1 acts downstream of two Rho-associated kinases (ROCKs), known as ROCK 1 and ROCK 2, which are elevated in early AD. Previous investigations had suggested that the activity of ROCKs is increased early and remains elevated in neurons throughout AD progression, potentially contributing to synaptic loss, the authors continued. Scientists have been trying to develop compounds that inhibit ROCK as a therapeutic strategy for AD, but such inhibitors have side effects, including lowering blood pressure to dangerous levels, and so they haven’t made into the clinic. “… critical questions remain regarding the role of ROCKs in AD and the contribution of ROCK1 or ROCK2 to the observed beneficial effects of pan-ROCK inhibitors,” the investigators continued.

Results from the team’s newly reported experiments in cultured rat brain neurons confirmed that ROCK1 and ROCK2 directly regulate dendritic spine length and density through different mechanisms, with ROCK2 kinase activity operating via a LIMK1 signaling pathway. The studies also showed that genetically blocking ROCK2 reduced dendritic spine loss in rat neurons exposed to amyloid β. Treating neurons with SR7826—a small molecule LIMK1 inhibitor that is in development as an anticancer drug—also blocked ROCK2-mediated reductions in spine density.

Given these findings the team hypothesized that chemically inhibiting LIMK1 might also modulate Aβ-induced spine degeneration. “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,” Herskowitz noted. Their initial experiments confirmed that treating cultured rat neurons using the LIMK1 inhibitor SR7826 prevented amyloid-β-induced dendritic spine loss. Encouragingly, subsequent tests in a mouse model of AD also confirmed that SR7826 treatment once a day for 10 days helped to boost dendritic spine density and length.

“Collectively, our findings link experimental models with human disease by demonstrating that Aβ-induced changes in ROCK2-LIMK1 signaling likely contribute to dendritic spine degeneration in AD,” the authors concluded. “Moreover pharmacologic inhibition of LIMK1 is identified as a rational therapeutic approach to protect spines from Aβ.”

“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,” Herskowitz commented. “This is one of the first scientific papers to suggest that LIMK1 might be a better target for intervention than the ROCK kinases. Another important aspect of this sort of target is that it could lead to an intervention before loss of cognitive function has begun. It could provide a protective effect to prevent damage or loss of dendritic spines.” Further studies will be needed to investigate the longer-term effects of LIMK1 inhibition and potential side effects.

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