01 January 2015

Stem Cells Help In Identifying New Treatments for Dementia

Researchers in Belgium are using induced pluripotent stem cell (iPSC) technology to create neurons that are targeted by dementia.

By studying these neurons, the scientists have found a defect that prevents normal neurodevelopment. Stem cells were taken from patients who has an inheritable type of dementia that is responsible for 50% of dementia cases for people below the age of 60.

Dementia is a neurological disorder that causes loss of brain function. Memory, language, behavior, judgement and how the patient thinks are affected by dementia. It is a serious loss of global cognitive ability in a previously unimpaired or normal person, beyond what might be expected from normal aging. It may be static dementia, the result of a unique global brain injury, or progressive dementia, resulting in long-term decline due to damage or disease in the body.

The most common type of dementia is Alzheimer's disease.

Usually associated with elderly patients, there are cases of dementia occurring to patients below the ages of 60/65.

The type of dementia that the Belgian scientists are studying is frontotemporal dementia. It is the result of damaged neurons in the frontal and temporal lobs which affects the patient's behavior, language, and emotions.

By reconstructing the damaged neurons using stem cells, the scientists identified the defective neuron pathway, the Wnt signalling pathway, that when genetically corrected and treated, restored the ability of the iPSCs to turn into cortical neurons.

This novel method may help scientist better understand the disease and create a cure or therapy for the disease.

Transforming Stem Cells

Belgian researchers have identified a new strategy for treating an inherited form of dementia after attempting to turn stem cells derived from patients into the neurons most affected by the disease. In patient-derived stem cells carrying a mutation predisposing them to frontotemporal dementia, which accounts for about half of dementia cases before the age of 60, the scientists found a targetable defect that prevents normal neurodevelopment. These stem cells partially return to normal when the defect is corrected.

The study appears in the December 31st issue of Stem Cell Reports, the official journal of the International Society of Stem Cell Research published by Cell Press.

"Use of induced pluripotent stem cell (iPSC) technology"--which involves taking skin cells from patients and reprogramming them into embryonic-like stem cells capable of turning into other specific cell types relevant for studying a particular disease--"makes it possible to model dementias that affect people later in life," says senior study author Catherine Verfaillie of KU Leuven.

Frontotemporal disorders are the result of damage to neurons in parts of the brain called the frontal and temporal lobes, gradually leading to behavioral symptoms or language and emotional disorders. Mutations in a gene called progranulin (GRN) are commonly associated with frontotemporal dementia, but GRN mutations in mice do not mimic all the features of the human disorder, which has limited progress in the development of effective treatments.

Video: What is Dementia?

"iPSC models can now be used to better understand dementia, and in particular frontotemporal dementia, and might lead to the development of drugs that can curtail or slow down the degeneration of cortical neurons," Verfaillie says.

Verfaillie and Philip Van Damme of the Leuven Research Institute for Neuroscience and Disease explore this approach in the Stem Cell Reports study by creating iPSCs from three patients carrying a GRN mutation. These immature cells were impaired at turning into mature, specialized cells called cortical neurons--the most affected cell type in frontotemporal dementia.

One of the top defective pathways in the iPSCs was the Wnt signaling pathway, which plays an important role in neuronal development. However, genetic correction or treatment with a compound that inhibits the Wnt signaling pathway restored the ability of the iPSCs to turn into cortical neurons. Taken together, the findings demonstrate that the GRN mutation causes the defect in cortical neuron formation by altering the Wnt signaling pathway.

"Our findings suggest that signaling events required for neurodevelopment may also play major roles in neurodegeneration," Van Damme says. "Targeting such pathways, as for instance the Wnt pathway presented in this study, may result in the creation of novel therapeutic approaches for frontotemporal dementia."

The researchers will now work to better understand what goes wrong in GRN-mutated cells, as well as identify precise molecular targets that could then be used for drug screens.


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Leuven Research Institute for Neuroscience and Disease
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