Tau and other proteins found in Alzheimer's disease spinal fluid are linked to retromer-mediated endosomal traffic in mice and humans.

Endosomal trafficking has emerged as a defective biological pathway in Alzheimer's disease (AD), and the pathway is a source of cerebrospinal fluid (CSF) protein accumulation. Nevertheless, the identity of the CSF proteins that accumulate in the setting of defects in AD's endosomal trafficking pathway remains unknown. Here, we performed a CSF proteomic screen in mice with a neuronal-selective knockout of the core of the retromer complex VPS35, a master conductor of endosomal traffic that has been implicated in AD. We then validated three of the most relevant proteomic findings: the amino terminus of the transmembrane proteins APLP1 and CHL1, and the mid-domain of tau, which is known to be unconventionally secreted and elevated in AD. In patients with AD dementia, the concentration of amino-terminal APLP1 and CHL1 in the CSF correlated with tau and phosphorylated tau. Similar results were observed in healthy controls, where both proteins correlated with tau and phosphorylated tau and were elevated in about 70% of patients in the prodromal stages of AD. Collectively, the mouse-to-human studies suggest that retromer-dependent endosomal trafficking can regulate tau, APLP1, and CHL1 CSF concentration, informing on how AD's trafficking pathway might contribute to disease spread and how to identify its trafficking impairments in vivo.