Researchers in Belgium have discovered a way to repair diseased brain cells in people with an inherited type of dementia for which there is currently no cure, a finding that could pave the way to new drug treatments for the disorder.
Studying stem cells with a mutation that predisposes people to the development of frontotemporal dementia — a form of the condition found in about half the dementia cases that develop before age 60 — the researchers identified a defect that interferes with normal neurological development.
When the defect was targeted and corrected, the stem cells partially returned to normal, they reported in the journal Stem Cell Reports.
Frontotemporal dementia is the result of damage to neurons in parts of the brain called the frontal and temporal lobes, areas generally associated with personality, behavior and language. In frontotemporal dementia, portions of these lobes atrophy or shrink, causing a range of symptoms and comorbidities including dramatic changes in personality and behavior, emotional and language disorders, and loss of motor functions (i.e., impairments in balance, coordination, walking, and other movements).
Past research has linked mutations in a gene called progranulin (GRN) with frontotemporal dementia, indicating this could be a potential target for treatment. However, opportunities to study GRN mutations in usual animal lab experiments have been very limited, as mice do not display all the symptoms of the human version of the disorder, the researchers explain.
Stem cells used to recreate neurons affected by disease
Instead of relying on animal tests, the new research involved creating human cells in a laboratory dish. To create the new dementia model, the scientists reprogrammed skin cells from three dementia patients into induced pluripotent stem cells (iPSCs), immature cells that mimic stem cells taken from early-stage embryos.
Like embryonic stem cells, iPSC’s have the potential to become any kind of body tissue. Each of the patients taking part in the study had a GRN mutation. The aim was to recreate damaged neurons in the laboratory.
But the researchers found that iPSCs derived from the patients’ were unable to generate cortical neurons, the cell type most affected by FTD. Cortical neurons are the cells responsible for most of the brain’s complex higher activity enabling thought, perception and voluntary movement.
Targeting Wnt pathway could lead to ‘novel therapeutic approaches for dementia’
The results indicate that defective GRN altered the Wnt signalling pathway, which plays an important role in neuronal development. However, inhibiting Wnt either with genetic correction or a drug compound restored the ability of the stem cells to convert into cortical neurons, the researchers found.
“Our findings suggest that signaling events required for neurodevelopment may also play major roles in neurodegeneration,” says study co-author Dr. Philip Van Damme of the Leuven Research Institute for Neuroscience and Disease. “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.”
Further investigation of what goes on in GRN-mutated cells could help identify some precise molecular targets for possible drug treatments for dementia, the researchers add.
Wnt signaling pathway and human diseases
These findings add to a growing line of research implicating the Wnt signaling pathway in the development of a diverse range of diseases including dementia and other neurodegenerative conditions, skin diseases, skeletal disorders, cardiovascular diseases, developmental disorders, and even cancer.
In another Mayo Clinic study published in September, researchers discovered that a defect in the Wnt pathway contributes to both overproduction of toxic proteins in the brains of Alzheimer’s disease patients as well as loss of communication between neurons — both significant contributors to this type of dementia.
In that study, deficient levels of low-density lipoprotein receptor-related protein 6 (LRP6) were linked with suppressed activity in the Wnt pathway, indicating that drugs aimed at restoring LRP6 and stimulating the Wnt pathway could offer a new approach to treating Alzheimer’s disease.