Neurodegenerative disease: New findings on NPC

Researchers from LMU University Hospital and the German Center for Neurodegenerative Diseases (DZNE) present new findings in the journal Science Translational Medicine on the mechanisms of Niemann-Pick Type C (NPC), a rare neurodegenerative disease that is associated with dementia and can manifest itself as early as childhood.

The research results are based on studies in mice, cell cultures and humans with NPC. They underline the role of inflammatory processes in this disease. The findings also point to a biomarker that could be useful for monitoring progression and assessing the success of treatment. Specifically, it is a molecule called TSPO. This can be detected in the brain using positron emission tomography (PET).

"We normally associate dementia with older people. However, there are also dementia diseases that manifest themselves in children and lead to death at the age of 30 or even earlier, such as Niemann-Pick type C," explains Dr. Sabina Tahirovic, neuroscientist at the DZNE site in Munich. Alongside her, Professor Matthias Brendel, an expert in neuroimaging at the LMU Hospital, also played a key role in the new study.

Inflammatory processes play a role

It is estimated that around 150 people in Germany are affected by this rare neurodegenerative disease. They have mutations in one of two specific genes that regulate fat metabolism. As a result, there is a harmful accumulation of fatty substances - known as lipids - in the brain and other organs. This in turn can trigger movement disorders as well as severe psychiatric and neurological symptoms - including dementia.

“It often takes years before NPC is diagnosed and numerous visits to the doctor are necessary. The relevant mutations are easy to detect, but often NPC is not initially considered because the disease is so rare,” says Tahirovic. Certain drugs that affect fat metabolism can alleviate the symptoms. So far, however, there are no therapies that can stop the disease permanently.

“Although we know the genetic causes of NPC, the mechanisms of disease development are still poorly understood. Our findings now underline that neuroinflammation is a decisive factor. This involves inflammatory processes that are mediated by the brain's immune system. We have also identified a potential biomarker for monitoring progression and the effect of treatment measures,” says the neuroscientist. “With the development of new therapeutics for NPC, we urgently need such metrics to capture clinical benefit and disease progression.”

A pathological cascade

Based on the results of previous studies, Tahirovic and her colleagues turned their attention to “microglia”: these cells are part of the brain's immune system and are therefore specialized in fighting pathogens and other threats. In NPC, however, they appear to do more harm than good. “We were able to show that microglia actively contribute to NPC pathology by triggering a harmful neuroinflammatory response in the brain,” says Tahirovic.

“We see these immune cells as part of a pathological cascade that also involves other brain cells and ultimately damages neurons. Current treatments for NPC aim to reduce the amount of lipids in the cells, as this accumulation is pathological. Our findings not only shed new light on basic disease mechanisms, they could also have practical implications for NPC patients.”

Lina Dinkel et al: Myeloid cell-specific loss of NPC1 in mice recapitulates microgliosis and neurodegeneration in patients with Niemann-Pick type C disease. Science Translational Medicine 2024