Does jammed-up protein recycling in neurons cause proteins to spill into the cerebrospinal fluid in Alzheimer’s disease? As reported in the November 25 Science Translational Medicine, scientists led by Scott Small at Columbia University, New York, identified 26 proteins that were released into the CSF when VPS35, the main protein of the retromer complex, was knocked out in the forebrains of mice. Lo and behold, among them were fragments of tau and of two BACE1 substrates, APLP1 and CHL1. The same fragments are found in the CSF of people with mild cognitive impairment and AD. The data indirectly link CSF tau to BACE1 activity, which may hint at a new mechanism of AD pathology.
“Together these findings suggest a relationship between pathological changes in neuronal endosomal trafficking and formation of tau species linked to Alzheimer’s,” Amy Pooler, now at Sangamo Therapeutics, San Francisco, told Alzforum.