Extracellular Tau Spreading

by Jesus Ávila, MD on 8 January 2016

The microtubule-associated protein tau is mainly expressed within neurons where it performs its physiological function of microtubule stability. However, extracellular tau is found in models of tau overexpression in which neuronal degeneration and cell death is prominent. The role of extracellular tau is under discussion. Extracellular tau could interact with cell receptors resulting in cell signaling and increase intracellular calcium, a toxic event. Thus, tau, apart from its well-established intracellular functions in microtubule stabilization and axonal transport, may possess in its extracellular form, an important alternative signaling role that could contribute to the neurodegenerative process in Alzheimer’s disease (AD). This role of extracellular tau may depend on whether it is in a monomeric or aggregated form. Tau plays a critical role in the pathogenesis of AD, and prominent tau pathology is present in several related disorders collectively known as tauopathies because of these shared histopathological/biochemical features. Development of tau pathology closely associates with progressive neuronal loss and cognitive decline. In the brains of AD patients, for instance, tau pathology follows an anatomically defined pattern described by the commonly used neuropathological Braak sequential staging.

Recent studies have shown that misfolding of tau in diseased brain leads to the appearance of abnormal conformations (and aggregation) of the protein that can be taken up by surrounding neurons. Accumulation of abnormal tau could be mediated by the spreading of seeds of the protein from cell to cell, pointing to the involvement of extracellular tau species as the main agent in the neuron-to-neuron propagation of neurofibrillary pathology and progression of tau toxicity that spreads throughout different brain regions in those disorders. This idea supports the concept that pathology initiates in a very small part of the brain many years before becoming symptomatic by spreading progressively to the whole brain within 15-20 years, perhaps reminiscent of some features of the prion protein propagation mechanism.

The fact that misfolded tau can be secreted and taken up by adjacent neurons calls for the development of novel therapeutic strategies aimed at blocking the propagation of tau pathology in the brain. Preventing the initial formation of the abnormal tau seeds or decreasing the amount of extracellular tau might block the subsequent propagation of tau aggregates, thus representing future potential therapeutic strategies.

However, key questions remain open and understanding the precise molecular mechanism underlying tau propagation is crucial for the development of therapeutics. Also, the precise relationship between tau release under physiological conditions and the propagation of pathology in AD and other tauopathies remains to be determined. At a basic level, more work should be done to understand the mechanisms for tau secretion in soluble or aggregated form, for tau uptake in neurons, or to confirm a possible tau transmission through the synaptic contacts for its cell-cell propagation. Thus, more research is needed to identify disease mechanisms driving release and propagation of tau pathology and to determine the impact of extracellular tau on cognitive decline during neurodegeneration. Finally, the relationship between tau post-translational modifications such as phosphorylation, glycosylation, acetylation, and truncation, among others with the cellular mechanisms of tau release and spreading must be elucidated.

Is secretion of fragmented and full-length tau by the same mechanism?

Last comment on 8 January 2016 by Alejandra Alonso, PhD

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Tau pathology in Alzheimer's disease (AD) and other tauopathies such as argyrophilic grain disease (AGD) propagates following a stereotypically defined pattern. As described by Dr. Avila in his blog post, accumulation of abnormal tau might be mediated through spreading of seeds of the protein from cell to cell and point to the involvement of extracellular tau species as the main agent in the interneuronal propagation of neurofibrillary lesions and spreading of tau toxicity throughout different brain regions in these disorders. Usually spreading of tau pathology is thought to occur from neuron to neuron following various pathways, including the trans-synaptic one [1-3]. However, recent reports suggest that glial cells could also be involved in tau spreading. Thus, working in tau transgenic mice, Maphis et al. [4] show that reactive microglia drive tau pathology in a cell-autonomous manner. In addition, Avila's group has reported that tau can be internalized by glial cells in vitro and in vivo [5] and showed colocalization of tau with microglia in postmortem AD brains. Finally, studies on a rapid tau propagation mouse model have shown that depletion of microglia dramatically suppresses tau propagation from the entorhinal cortex to the dentate gyrus [6]. Moreover, they also show that the mechanism by which microglia spread tau is mediated by secretion of exosomes and inhibiting exosome synthesis reduces tau propagation. Thus, the potential role of microglia in the internalization and propagation of tau might be relevant when designing therapeutic strategies to enhance clearance of extracellular tau in neurodegenerative disease characterized by the accumulation of this protein.

References
[1] Gómez-Ramos A, Díaz-Hernández M, Rubio A, Miras-Portugal MT, Avila J (2008) Extracellular tau promotes intracellular calcium increase through M1 and M3 muscarinic receptors in neuronal cells. Mol Cell Neurosci 37, 673-681.
[2] de Calignon A, Polydoro M, Suárez-Calvet M, William C, Adamowicz DH, Kopeikina KJ, Pitstick R, Sahara N, Ashe KH, Carlson GA, Spires-Jones TL, Hyman BT (2012) Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 73, 685-697.
[3] Liu L, Drouet V, Wu JW, Witter MP, Small SA, Clelland C, Duff K (2012) Trans-synaptic spread of tau pathology in vivo. PLoS One 7, e31302.
[4] Maphis N, Xu G, Kokiko-Cochran ON, Jiang S, Cardona A, Ransohoff RM, Lamb BT, Bhaskar K (2015) Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain 138(Pt 6), 1738-1755.
[5] Bolós M, Llorens-Martín M, Jurado-Arjona J, Hernández F, Rábano A, Avila J (2016) Direct evidence of internalization of tau by microglia in vitro and in vivo. J Alzheimers Dis, doi: 10.3233/JAD-150704.
[6] Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, Wolozin B, Butovsky O, Kügler S, Ikezu T (2015) Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci 18, 1584-1593.

My speculation is that most probably tau is not secreted but shows up in interstitial and cerebrospinal fluids through neuronal degeneration. In normal adult brain there is a balance between tau released as a result of the degeneration of neurites and neurons and its clearance from the brain. With age this balance is progressively and slightly shifted to enhanced release and decreased clearance. In Alzheimer’s disease brain some of the tau released from degenerating/degenerated neurons is abnormally hyperphosphorylated and aggregated as “tau seeds”. Tau seeds are less efficiently cleared and some of them are taken up in a random fashion by healthy neurons in the vicinity, where the seeds sequester the intraneuronal normal tau and convert it into tau pathology. The spatial environment in the hippocampus seems to be far more conducive than other areas of the cerebral cortex for the uptake of the seeds and hence the maximal pathology in the hippocampus. Tau immunotherapy has the potential to attenuate the spread of neurofibrillary pathology by reducing the number of tau seeds from the extracellular space.

The biology of tau deserves a very close look. Tau, very well described and studied as a microtubule associated protein, is involved in many neurodegenerative diseases, such as Alzheimer’s disease, and more recently, tau has regained “fame” when it was discovered in the brain of NFL players as the product of traumatic brain injury. Because of the widespread participation of tau in pathology, these diseases are collectively known as tauopathies. Despite their diverse phenotypic manifestations, brain dysfunction, and degeneration, these tauopathies are linked to the progressive accumulation of filamentous hyperphosphorylated tau inclusions, a.k.a. neurofibrillary tangles, and these inclusions, together with the absence of other disease-specific neuropathological abnormalities (except for AD), provide circumstantial evidence implicating abnormal tau in disease onset and/or progression.

AD, the most common tauopathy, has a well-defined progression that suggests that pathological tau pathology induced by its hyperphosphorylation might spread following the characteristics of anatomical connectivity in the brain. The idea of tau spreading has been in the field for a long time and as early as 1997 when the group of Dr. Cotman proposed that hyperphosphorylated tau could spread with a trans-neuronal mechanism. Nevertheless, the molecular mechanism of tau spreading is today the focus of intense research due to the potential therapeutic implications. As Professor Avila pointed out, extracellular tau is present in a soluble or aggregated form. The presence of tau was also detected in vesicles, exosomes, or ectosomes, found in cerebrospinal fluid of AD patients. Interestingly, the tau found in these structures is abnormally phosphorylated, similar to tau present in neurofibrillary tangles. Tau’s conformational change, due to hyperphosphorylation, appears to be a critical first step in the process of neurodegeneration, and the acquired conformation can be “transferred” to the normal proteins. Very low amounts of abnormal tau can disrupt the microtubules, the train tracks of the neuron, inducing an interruption of the normal transport and marking a retrograde neurodegeneration. There is another piece in this puzzle, tau can be found also in the nucleus, and we still do not know what tau function is in the nucleus, if any. Neurodegeneration associated with tau does not only concern dementia in aging, it is a problem that can affect young football players and war veterans, and the research efforts and resources should be invested in studying the biology of this remarkable protein that will give us clues for therapeutical interventions.

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