Extracellular Monomeric and Aggregated Tau Efficiently Enter Human Neurons through Overlapping but Distinct Pathways

Abstract

SummaryIn Alzheimer’s disease, neurofibrillary tangle pathology appears to spread along neuronal connections, proposed to be mediated by the release and uptake of abnormal, disease-specific forms of microtubule-binding protein tau MAPT. It is currently unclear whether transfer of tau between neurons is a toxic gain-of-function process in dementia or reflects a constitutive biological process. We report two entry mechanisms for monomeric tau to human neurons: a rapid dynamin-dependent phase typical of endocytosis and a second, slower actin-dependent phase of macropinocytosis. Aggregated tau entry is independent of actin polymerization and largely dynamin dependent, consistent with endocytosis and distinct from macropinocytosis, the major route for aggregated tau entry reported for non-neuronal cells. Anti-tau antibodies abrogate monomeric tau entry into neurons, but less efficiently in the case of aggregated tau, where internalized tau carries antibody with it into neurons. These data suggest that tau entry to human neurons is a physiological process and not a disease-specific phenomenon.

The uptake of tau amyloid fibrils is facilitated by the cellular prion protein and hampers prion propagation in cultured cells

“…A similar hypothesis has been proved true in the case of intercellular transfer of tau amyloids through tunneling nanotubes, where extracellular tau species (monomers and fibrils) activated the formation of new nanotubes and therefore facilitated fibrillar tau transport between neurons (15). On the other hand, protein aggregates (tau and synuclein) are trafficked in early endosomes and lysosomes after the internalization (20,40,41). The need of the cell to deal quickly with a large amount of exogenous and potentially dangerous material might clog the degradation system, with subsequent impact on the normal turnover of the endogenous proteins.…”

Filamentous aggregates are fragmented by the proteasome holoenzyme

“…in a scenario when aggregates enter the host cell from the extracellular environment (e.g. [32][33][34]), the proteasomal mechanisms that are involved in clearing cytosolic misfolded proteins to prevent intracellular aggregate formation may be distinct from its fibril-fragmenting function.…”

LRRK2 and Rab10 Coordinate Macropinocytosis to Mediate Immunological Responses in Phagocytes

“…Macropinocytosis can occur in non-phagocytic cells as well, usually in acute response to growth factors. Possible roles include the uptake and turn-over of misfolded proteins in Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) [3][4][5] . Without knowledge of proteins that specifically regulate macropinocytosis in endocytosis, most studies have explored the process using small molecule inhibitors EIPA (5-(N-Ethyl-N-isopropyl)amiloride) and rottlerin 6,7 .…”