Tau interacts with Golgi membranes and mediates their association with microtubules

Abstract

Tau, a microtubule-associated protein enriched in the axon, is known to stabilize and promote the formation of microtubules during axonal outgrowth. Several studies have reported that tau was associated with membranes. In the present study, we further characterized the interaction of tau with membranous elements by examining its distribution in subfractions enriched in either Golgi or endoplasmic reticulum membranes isolated from rat brain. A subfraction enriched with markers of the medial Golgi compartment, MG160 and mannosidase II, presented a high tau content indicating that tau was associated with these membranes. Electron microscope morphometry confirmed the enrichment of this subfraction with Golgi membranes. Double-immunogold labeling experiments conducted on this subfraction showed the direct association of tau with vesicles labeled with either an antibody directed against MG160 or TGN38. The association of tau with the Golgi membranes was further confirmed by immunoisolating Golgi membranes with an anti-tau antibody. Immunogold labeling confirmed the presence of tau on the Golgi membranes in neurons in vivo. Overexpression of human tau in primary hippocampal neurons induced the formation of large Golgi vesicles that were found in close vicinity to tau-containing microtubules. This suggested that tau could serve as a link between Golgi membranes and microtubules. Such role for tau was demonstrated in an in vitro reconstitution assay. Finally, our results showed that some tau isoforms present in the Golgi subfraction were phosphorylated at the sites recognized by the phosphorylation-dependent antibodies PHF-1 and AT-8.

Untangling the role of tau in Alzheimer’s disease: A unifying hypothesis

“…Disease-associated tau interactions with the membrane have also been showed in vivo [168], and may involve the tau N-terminus interacting with and being phosphorylated by srk family kinases such as fyn [75][76][77]175]. This pathway is consistent with demonstrations by LeClerc and coworkers showing that in both tau overexpression and in AD, tau becomes localized to the Golgi despite its lack of an ERtargeting signal sequence [176,177]. Finally, there is increasing evidence that vulnerable cellular protein turnover pathways (e.g.…”

Starvation and inhibition of lysosomal function increased tau secretion by primary cortical neurons

“…Several unconventional secretory pathways exist and therefore different tau species might have access to distinct pathways8. Furthermore, several studies including ours have reported that two pools of tau, a cytosolic and membranous one are present in neurons44454647. Each of these pools could have access to different secretory pathways in starved neurons.…”

In VivoMicrodialysis Reveals Age-Dependent Decrease of Brain Interstitial Fluid Tau Levels in P301S Human Tau Transgenic Mice

“…Besides tau, there are increasing numbers of intracellular proteins that lack ER signal sequences but reach the extracellular spaces via an unconventional secretion pathway (Nickel, 2010). Even though tau lacks a transmembrane or obvious secretion signal sequence, some tau has been observed in membranous compartments such as the Golgi body, plasma membranes, and mitochondria, which could be linked to secretion (Jung et al, 1993; Brandt et al, 1995; Farah et al, 2006). Exosome-mediated secretion, which has been suggested as a mechanism of α -synuclein secretion, could also play a role (Emmanouilidou et al, 2010).…”