C-Terminally Truncated Forms of Tau, But Not Full-Length Tau or Its C-Terminal Fragments, Are Released from Neurons Independently of Cell Death

Abstract

Recent evidence suggests that tau aggregation may spread via extracellular release and subsequent uptake by synaptically connected neurons, but little is known about the processes by which tau is released or the molecular forms of extracellular tau. To gain insight into the nature of extracellular tau, we used highly sensitive ELISAs, which, when used in tandem, are capable of differentiating between full-length (FL) tau, mid-region-bearing fragments, and C-terminal (CT) fragments. We applied these assays to the systematic study of the conditioned media of N2a cells, induced pluripotent stem cell-derived human cortical neurons, and primary rat cortical neurons, each of which was carefully assessed for viability. In all three neuronal models, the bulk of extracellular tau was free-floating and unaggregated and Ͻ0.2% was encapsulated in exosomes. Although most intracellular tau was FL, the majority of extracellular tau was CT truncated and appeared to be released both actively by living neurons and passively by dead cells. In contrast, only a small amount of extracellular tau was aggregation-competent tau (i.e., contained the microtubule-binding regions) and this material appears to be released solely due to a low level of cell death that occurs in all cell culture systems. Importantly, amyloid ␤-protein (A␤)-induced neuronal compromise significantly increased the quantity of all forms of extracellular tau, but the presence of A␤ before detectable cell compromise did not increase extracellular tau. Collectively, these results suggest that factors that induce neuronal death are likely to be necessary to initiate the extracellular spread of tau aggregation.

The release and trans-synaptic transmission of Tau via exosomes

“…It is worth noting that hypophosphorylated intact Tau was detected in conditioned medium of neuronal cultures in a previous study [11], although such extracellular Tau was demonstrated to be non-exosome associated, as Tau is barely detected in exosomal preparations, probably due to the limited material loaded. By contrast, another report stated that only C-terminally truncated Tau lacking the microtubule binding domain is released by cultured neurons or other types of cells [50] and a small fraction of extracellular Tau (<0.2%) is indeed present in exosomes. The cause of the discrepancy (truncated Tau v.s.…”

Propagation of Aß pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies

“…There is evidence that the N-terminal fragments of tau [13] or the "C-terminally truncated forms of Tau" [69] are secreted into the extracellular space. This extracellular tau is regulated by neuronal activity [99] and could modulate Aβ secretion [13]-although data are contradictory [69].…”

“…This extracellular tau is regulated by neuronal activity [99] and could modulate Aβ secretion [13]-although data are contradictory [69].…”

Presence of a carboxy-terminal pseudorepeat and disease-like pseudohyperphosphorylation critically influence tau’s interaction with microtubules in axon-like processes

“…, 2015) and may produce neurotoxic fragments (Park and Ferreira, 2005; Lang et al. , 2014), generate products that show increased release from neurons (Kanmert et al. , 2015), or produce fragments with a modified MT interaction (Derisbourg et al.…”