Scientists uncover cellular mechanism driving both rare childhood dementia and Alzheimer's disease

Researchers at the University of California San Diego have discovered a cellular mechanism that contributes to brain degeneration in both a rare childhood disorder and Alzheimer's disease. This pathway involves the brain's immune cells, known as microglia, responding to waste buildup within cells. In individuals with Sanfilippo syndrome type A, a lack of the enzyme sulfamidase leads to lysosomal dysfunction, causing debris to accumulate in microglia.

When these cells become clogged with fats and proteins, they lose their ability to protect neurons. The study found that a family of proteins called MITF/TFE act as master genetic switches that flip from an "off" to an "on" position when lysosomes in microglia become overburdened. This triggers a major change in the microglia's genetic program, ultimately leading to inflammation and neuron death.

Surprisingly, the same MITF/TFE switches are activated in microglia of people with Alzheimer's disease when waste accumulates. This suggests that the stress response caused by lysosomal failure in MPS IIIA is also occurring in the aging brains of Alzheimer's patients. The researchers believe that lysosomes alone are sufficient to cause neurodegeneration in rare disorders like MPS IIIA, and that the same process may be contributing to major diseases like Alzheimer's.

By targeting the MITF/TFE protein family, scientists may develop new drug therapies to maintain microglia in a protective state and prevent further brain damage.