Relative to control cells (left), cells short on VPS35 (right) accumulate more BACE1 (red) in endosomes (green).
Relative to control cells (left), cells short on VPS35 (right) accumulate more BACE1 (red) in endosomes (green).
Sluggish recycling of a protein-slicing enzyme could promote Alzheimer's disease (AD), show.
Aβ, the protein that accumulates in the brains of AD patients, is formed when enzymes cut up its parental protein, known as amyloid precursor protein. One of those enzymes is β-secretase or BACE1. BACE1 cycles between the Golgi apparatus and the plasma membrane, traveling through endosomes on the way. A protein complex called the retromer helps transport proteins from endosomes to the Golgi. Previous studies have found reduced levels of two retromer components, including the protein VPS35, in the brains of AD patients.
To find out whether VPS35 affects AD, the team crossed two mouse lines to create animals that are prone to many AD symptoms and generate half the normal amount of VPS35. The mice displayed AD-like abnormalities earlier than their parental strains, and their brains accumulated more Aβ.
Cells lacking VPS35 carried extra BACE1 in their endosomes. BACE1 is more active in the acidic interior of endosomes than in the more basic surroundings of the Golgi apparatus. Thus, by leaving more BACE1 trapped in endosomes, the decline in VPS35 levels could spur the formation of more Aβ. Although no VPS35 mutations have so far turned up in AD patients, the protein's level in the brain dwindles with age in mice. The researchers suspect that certain AD risk factors, such as oxidative stress, also diminish VPS35 levels in the brain.
