Researchers Identify Potential Treatment for Patients at Risk for Alzheimer’s Disease

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.

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MBF Bioscience research team contributes novel dendritic spine analysis in study published in Science

Combination of new microscopy and expansion tissue preparation methods facilitate better and faster analysis of subcellular neural elements.

Today, the journal Science published a paper authored by a research team led by Dr. Ed Boyden of MIT and Nobel Prize recipient Dr. Eric Betzig of Janelia Research Campus. Among the authors are MBF Bioscience Scientific Director Dr. Susan Tappan and Senior Software Engineer Alfredo Rodriguez. In the paper, the researchers introduce new analyses for neural circuits at nanoscale resolutions.

Combining microscopy methods that create high resolution 3D images from whole brains and tissue that have been made physically larger, the researchers imaged a mouse cortex and fruit fly brain in their study “Cortical column and whole-brain imaging of neural circuits with molecular contrast and nanoscale resolution (Gao et al, 2019).”

By creating enhanced processing and analysis tools in MBF Bioscience’s Stereo Investigator and Neurolucida 360 software, Dr. Tappan and Mr. Rodriguez analyzed these images to obtain comprehensive morphometrics of delicate dendritic spines at a greater accuracy than ever before.

GAO ET AL./SCIENCE 2019

“We combined expansion microscopy and lattice light sheet microscopy (ExLLSM) to image the nanoscale spatial relationships between proteins across the thickness of the mouse cortex or the entire Drosophila brain, including synaptic proteins at dendritic spines, myelination along axons, and presynaptic densities at dopaminergic neurons in every fly neuropil domain.” (Gao et al, 2019)

While several forms of microscopy exist that have the ability to image subcellular neural elements, scientists say that each of these methods is lacking in one way or another. According to the paper, the combination of expansion microscopy with lattice-light sheet microscopy gives the most effective results, while considerably decreasing the time spent carrying out the experiment.

“I believe this type of imaging represents a major milestone in terms of the accuracy that can be achieved in dendritic spine morphometry from light microscopy,” Mr. Rodriguez said.

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Scientists Discover New “Rosehip” Neuron in Human Brain

Neurolucida and Neurolucida Explorer Used for 3D Reconstruction and Quantitative Analysis

Researchers used Neurolucida to reconstruct a newly discovered type of neuron found only in the human brain, according to a study published in the journal Nature Neuroscience. Known as “rosehip” neurons because of the way they resemble a rose after its petals have fallen off, these cells feature compact, bushy axonal arborizations.

Found in the first layer of the cerebral cortex, a highly complex brain region that is thought to play an important role in consciousness, “rosehip neurons” have not been seen in mice or other laboratory animals, and scientists suggest that they may exist only in humans. Classified as inhibitory neurons, these brain cells form synapses with pyramidal neurons in layer 3 of the cerebral cortex, according to the study.

Led by Dr. Ed Lein, of the Allen Institute for Brain Science, and Dr. Gábor Tamás, a neuroscientist at the University of Szeged in Szeged, Hungary, the research team used Neurolucida to reconstruct rosehip neurons in 3D. Their reconstructions revealed that these cells display morphological characteristics that differ significantly from other types of cells found in this region of the brain.

Scientists used Neurolucida and Neurolucida Explorer to reconstruct and analyze a rosehip neuron. Image Credit: Tamas Lab, University of Szeged

Using Neurolucida Explorer to quantitatively analyze their cell reconstructions, the researchers observed similar numbers of primary dendrites in both rosehip neurons and basket cells, but fewer compared to neurogliaform cells. Meanwhile, they calculated similar total dendritic length and frequency of dendritic nodes in rosehip neurons and neurogliaform cells, but recorded differences in basket cells.

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