Shared cellular pathway drives neurodegeneration in rare childhood dementia and Alzheimer’s

Researchers at University of California San Diego and their colleagues have identified a key cellular pathway that drives brain degeneration in both a rare childhood disorder and the far more common Alzheimer's disease. The study, published in Immunity, reveals how the brain's immune cells respond to waste buildup and provides a novel roadmap for understanding and treating neurodegenerative conditions.

Children with Sanfilippo syndrome type A, also known as Mucopolysaccharidosis Type IIIA (MPS IIIA), experience seizures and dementia among other symptoms, leading to early death. The condition is caused by a single gene variant that blocks the production of the enzyme sulfamidase. Normally, tiny structures within cells called lysosomes use sulfamidase to break down nutrients into usable energy, destroy harmful invaders like bacteria, and recycle old cell parts for reuse. In the absence of the enzyme, debris accumulates.

The researchers studied a mouse model of MPS IIIA, finding that while this waste builds up in many cell types, microglia - the brain's dedicated immune cells - are impacted the most. These cells expand as they become clogged with fats and proteins, losing their ability to protect neurons.

The researchers identified a family of proteins, known as MITF/TFE, that act as master genetic switches. When lysosomes in microglia become overburdened and stressed, these switches are flipped from the "off" to the "on" position, triggering a massive change in the microglia's genetic program in order to protect the brain. But this response eventually becomes maladaptive, fueling inflammation and contributing to the death of neurons.