Hyperphosphorylation and Cleavage at D421 Enhance Tau Secretion

Abstract

It is well established that tau pathology propagates in a predictable manner in Alzheimer’s disease (AD). Moreover, tau accumulates in the cerebrospinal fluid (CSF) of AD’s patients. The mechanisms underlying the propagation of tau pathology and its accumulation in the CSF remain to be elucidated. Recent studies have reported that human tau was secreted by neurons and non-neuronal cells when it was overexpressed indicating that tau secretion could contribute to the spreading of tau pathology in the brain and could lead to its accumulation in the CSF. In the present study, we showed that the overexpression of human tau resulted in its secretion by Hela cells. The main form of tau secreted by these cells was cleaved at the C-terminal. Surprisingly, secreted tau was dephosphorylated at several sites in comparison to intracellular tau which presented a strong immunoreactivity to all phospho-dependent antibodies tested. Our data also revealed that phosphorylation and cleavage of tau favored its secretion by Hela cells. Indeed, the mimicking of phosphorylation at 12 sites known to be phosphorylated in AD enhanced tau secretion. A mutant form of tau truncated at D421, the preferential cleavage site of caspase-3, was also significantly more secreted than wild-type tau. Taken together, our results indicate that hyperphosphorylation and cleavage of tau by favoring its secretion could contribute to the propagation of tau pathology in the brain and its accumulation in the CSF.

The aggregation of mutant p53 produces prion-like properties in cancer

“…3 Intracerebral injections of Tau aggregates into mice also induced the aggregation of native Tau, similarly suggesting that transmission between cells could occur. 40 Whereas the mechanisms behind cell-to-cell transmission are still being investigated, some light has been shed on the active release of fibrils 41 from one cell into the media, the release of these fibrils into recipient cells 42 and their direct contact with other cells or their involvement with exosomes. 43 Laboratory experiments demonstrated the host-to-host transmission of AA amyloidosis.…”

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

“…However, tau levels do not correlate with lactate dehydrogenase or tubulin release into the media [53,54], implying that release is not due to increased cell death. This observation is supported by evidence that monomeric tau secretion is an active process, as tau release is inhibited at low temperatures [53], and has been linked to synaptic activity [55]. It is still quite Fig.…”

“…In contrast to evidence for exosome-mediated release, immunoprecipitation of tau fibrils from culture media supports direct release of free fibrils into the extracellular space [42,53]. Finally, an anti-tau antibody has been observed to block cell-cell propagation of aggregation "donor" to "recipient" cells by preventing cell uptake [42].…”

“…2 Several explanations have been proposed for tau release. These include unconventional secretion directly into the media [53,54], vesicle-associated release [56] and exosomeassociated release [57,58]. While certain studies show a subset of secreted tau is found in the exosomal fraction of conditioned media [58], others show little to no tau in this fraction [53,54].…”

Transmission of Tau Pathology from Human to Rodent Brain: How to Humanise Animal Models for Alzheimer’s Disease Research

“…Tau is constitutively released from neurons under physiological conditions [71,[76][77][78][79][80][81][82][83][84][85][86][87][88]. The secretion is multifaceted, involving diverse intracellular components such as autophagosomes, Golgi, endosomes, ectosomes, lysosomes, microsomes and endoplasmic reticulum [89].…”