Neurolucida 360 Used to Analyze Dendrites and Dendritic Spines
Amyloid plaques and tau tangles are the hallmarks of Alzheimer’s disease (AD) pathology, but synapse loss is what causes cognitive decline, scientists say. In a paper published in Science Signaling, researchers at the Herskowitz Lab, at the University of Alabama at Birmingham, used Neurolucida 360 to analyze spine density and dendritic length in hAPP mice — a mouse model of AD. Their findings describe a treatment that could protect against synapse loss and prevent the onset of dementia in patients at risk for Alzheimer’s disease.
Targeting LIMK1 to Protect Against Dendritic Damage
In their study, the scientists targeted LIMK1, an enzyme that regulates the size and density of dendritic spines. Previous studies have shown that in animal models of AD, LIMK1 activity is increased, causing synaptic hyperactivity and dendritic damage. After confirming this phenomenon, the research team set out to find a way to inhibit LIMK1, which lies downstream of two other important players in dementia pathology — the Rho-associated kinases known as ROCK1 and ROCK2.
Representative maximum-intensity high-resolution confocal microscope images of dye-filled dendrites, from CA1 hippocampal neurons in mice, after deconvolution and corresponding 3D digital reconstruction models of dendrites. Scale bar, 5 μm. Colors in digital reconstructions correspond to dendritic protrusion classes: blue, thin spines; orange, stubby spines; green, mushroom spines; and yellow, dendritic filopodia.
Previous studies have shown that severe side effects including fatally low blood pressure are associated with the inhibition of ROCK1 and ROCK2, so the researchers looked further down the signaling pathway to the LIMK1 point, potentially discovering a truly valid target in the fight to prevent dementia onset.
Since LIMK1 has also been a target in cancer treatment, the researchers turned to SR7826, an experimental drug currently in development to treat cancer patients. They found that administering SR7826 suppressed LIMK1 activity and protected dendritic morphology against the damage commonly seen in a brain afflicted with dementia. By reconstructing the mouse neurons with Neurolucida 360, they observed increased dendritic spine length and density in the experimental group, compared to controls.