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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Dying neurons in Alzheimer’s patients show signs of improvement after gene therapy

nucleus basalis of Meynert

Micrograph of cholinergic neurons in the nucleus basalis of Meynert. Image from Wikipedia.

 

Cholinergic neurons degenerate at devastating rates in Alzheimer’s disease, but Dr. Mark Tuszynski and his team at the University of California, San Diego may have found a way to slow the decline.

Their study, published in JAMA Neurology, reports that nerve growth factor gene therapy increased the size, axonal sprouting, and signaling of cholinergic neurons in 10 Alzheimer’s disease patients.

The patients were enrolled in a clinical trial between 2001 and 2012. Ex vivo and in vivo methods of gene therapy were used to deliver nerve growth factor – a protein that protects neurons and stimulates growth – to the patients. Eight received an implant of their own skin cells that were genetically modified to express nerve growth factor (ex vivo ) and two patients received injections that induced neurons already in the brain to express nerve growth factor (in vivo). In all 10 patients, gene therapy was delivered to the nucleus basalis of Meynert – part of the basal forebrain rich in cholinergic neurons that undergoes degeneration during Alzheimer’s disease. 

The patients’ survival time ranged from one to 10 years. After they had died, researchers analyzed the effects of nerve growth factor on cholinergic neurons.

The axons of cholinergic neurons, labeled with p75, grew toward the source of the nerve growth factor in all 10 patients. To determine if there was a change in cell size, researchers used the nucleator probe in Stereo Investigator to analyze cholinergic neurons of 3 patients who received gene therapy via the ex vivo method in one hemisphere – the other hemisphere was used as a control. Results from Stereo Investigator showed that cell bodies were larger in the treated hemisphere vs. the untreated hemisphere.

Finally, to find out if nerve growth factor induced signaling within cells, the researchers analyzed the amount of CREB and c-fos – markers for cell activation – in 2 patients who received nerve growth factor in vivo. An elevated amount of CREB and c-fos was found when compared to control regions. Neurons exhibiting tau pathology also expressed nerve growth factor, indicating that degenerating cells could respond to nerve growth factor gene therapy.

A phase 2 clinical study is currently under way to report cognitive outcomes in patients with Alzheimer’s disease.

“Collectively, these anatomical findings support the rationale for clinical trials to test the hypothesis that sustained growth factor delivery over time can reduce cell degeneration and stimulate cell function in chronic neurodegenerative disorders, thereby slowing functional decline,” Tuszynski, et al.

Tuszynski, M.H., Yang, J.H., Pay, M.M., Masliah, E., Barba, D., U, H.S., Conner, J.M., Kobalka, P., Roy, S., and Nagahara A.H. (2015). Nerve Growth Factor Gene Therapy: Activation of Neuronal Responses in Alzheimer Disease. JAMA Neurology, published online August 24, 2015. DOI: 10.1001/jamaneurol.2015.1807.

Higher levels of pTau found in Alzheimer’s disease patients with psychosis

murray_ptau

An image of neurofibrillary tangles and neuropil threads

People with Alzheimer’s disease suffer from severe memory loss and often have problems focusing, reasoning, and communicating. About half of all Alzheimer’s patients also experience delusions and hallucinations, this is called Alzheimer’s disease with psychosis, and scientists at the University of Pittsburgh are learning more about this severe version of the disease.

In a recent study, researchers at Dr. Robert Sweet’s lab zeroed in on a protein called tau, which forms tangles in the brains of Alzheimer’s patients, and along with amyloid plaques is one of the major hallmarks of the disease. But despite being involved in these pathological conditions, tau and amyloid may instigate other processes as well – namely, synaptic toxicity, which the authors say is “the strongest correlate of cognitive decline in Alzheimer’s disease.”

Recent research suggests that amyloids (misfolded proteins) drive the deterioration of synapses, but phospho-tau (tau, which has undergone phosphorylation), enables the process. So in their study the Pittsburgh research team analyzed the presence of tau in the prefrontal cortex, a region of the brain involved in higher processes, of 45 Alzheimer’s disease patients with and without psychosis.

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Neurolucida Helps Scientists Discover that Gorillas are Relevant in the Study of Alzheimer’s Disease

Cortical neurons containing tau termed neurofibrillary tangle seen in the human brain with Alzheimer's disease. The researchers used Neurolucida to count and chart similar neurons in the gorilla brain. 

Cortical neurons containing tau, termed neurofibrillary tangle, seen in the human brain with Alzheimer’s disease. The researchers used Neurolucida to chart similar lesions in the gorilla brain.

Humans and gorillas are approximately 98% identical on a genetic level, however there is little published research exploring Alzheimer’s disease pathology in gorillas. A new paper reports that gorillas display similarities in advanced age to humans  ̶  including the presence of Alzheimer’s disease precursors like amyloid-beta (Aβ) plaques and tau lesions.

The study, published in the Journal of Comparative Neurology, provides evidence of Alzheimer’s disease precursors in the western lowland gorilla. Their findings broaden the scientific community’s understanding of the aging brain of some our closest living relatives and offer new insights for Alzheimer’s disease research.

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