Interneuronal Transfer of Human Tau Between Lamprey Central Neurons in situ

Abstract

The mechanisms by which tau-containing lesions are propagated between adjacent and synaptically interconnected parts of the brain are a potentially important but poorly understood component of human tauopathies such as Alzheimer's disease, Pick's disease, and corticobasal degeneration. Since the utility of currently available transgenic models for studying intercellular aspects of tauopathy is limited by their broad patterns of tau expression in the central nervous system, we used an in situ tauopathy model that replicates tau-induced cytodegeneration in identified neurons on a tau-negative background to determine whether tau secretion or interneuronal transfer might play a role in lesion propagation. We found that the N-terminal half of tau is required for tau secretion and is efficiently exported to the extracellular space and adjacent neurons at relatively low levels of overexpression. By contrast, full-length tau is secreted by a separate mechanism that is correlated with phosphorylation of tau at tyrosine 18 and dendritic degeneration, is exacerbated by tauopathy mutations, and blocked by mutations that inhibit tau:tau interactions. Anterograde transneuronal tau movement occurred with the expression of tau containing the P301L tauopathy mutant, but not with wild type tau isoforms. Our results are consistent with recent studies suggesting a role for molecular "templating" in the propagation of neurofibrillary lesions and provide a novel conceptual and experimental basis for studying the mechanisms of interneuronal propagation and toxicity in human neurodegenerative disease.

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

“…The propensity of tau to oligomerize may well be a factor in favoring its secretion, since the presence of tauopathy mutations also favor secretion [183,192,193] and uptake [195].…”

“…mechanism [178] and the resulting pattern of extracellular accumulation and transport [193]. In the lamprey model, tau secretion occurs before the onset of degenerative cellular changes [192,193], suggesting that extracellular tau in AD brain and CSF is very likely due to secretion rather than passive release from dead or dying neurons as has been commonly been assumed [166,194].…”

“…It now appears that tau can be secreted from neurons in situ by multiple cellular pathways [179,192] and that the presence or absence of the MTBR is an important determinant of both the secretion Figure 1. Proteomic analysis of exosomes in neuroblastoma cells overexpressing 4R0N tau suggests links between tau secretion, AD, autophagy abnormalities and APP misprocessing.…”

Proteopathic tau seeding predicts tauopathy in vivo

“…This aspect suggests a role for transcellular spread of a pathogenic agent via neural connections. Our laboratory and others have previously hypothesized that tau aggregates-or seeds-serve as this agent of spread, transmitting the aggregated state from cell to cell via prion-like mechanisms (6)(7)(8)(9)(10)(11)(12)(13)(14)(15).…”

Synaptic Function and Dysfunction in Alzheimer’s Disease

“…Extracellular tau could be toxic by increasing intracellular calcium into neighboring neurons [82]. The presence of extracellular tau can be due to other causes, for example exocytosis; the N-terminal region of tau seems to be required for its secretion [83]. Neuronal toxicity may be caused by tau aggregates, even small and soluble aggregates in the form of oligomers, which have been identified in AD brain [84].…”