The potential role of glial cells in driving the prion-like transcellular propagation of tau in tauopathies

Abstract

Dementia is one of the leading causes of death worldwide, with tauopathies, a class of diseases defined by pathology associated with the microtubule-enriched protein, tau, as the major contributor. Although tauopathies, such as Alzheimer's disease and Frontotemporal dementia, are common amongst the ageing population, current effective treatment options are scarce, primarily due to the incomplete understanding of disease pathogenesis. The mechanisms via which aggregated forms of tau are able to propagate from one anatomical area to another to cause disease spread and progression is yet unknown. The prion-like hypothesis of tau propagation proposes that tau can propagate along neighbouring anatomical areas in a similar manner to prion proteins in prion diseases, such as Creutzfeldt-Jacob disease. This hypothesis has been supported by a plethora of studies that note the ability of tau to be actively secreted by neurons, propagated and internalised by neighbouring neuronal cells, causing disease spread. Surfacing research suggests a role of reactive astrocytes and microglia in early pre-clinical stages of tauopathy through their inflammatory actions. Furthermore, both glial types are able to internalise and secrete tau from the extracellular space, suggesting a potential role in tau propagation; although understanding the physiological mechanisms by which this can occur remains poorly understood. This review will discuss the current literature around the prion-like propagation of tau, with particular emphasis on glial-mediated neuroinflammation and the contribution it may play in this propagation process.

Keywords: Alzheimer’s disease; Astrocytes; Microglia; Neuroinflammation; Prion-like hypothesis.

Fig. 1

Alternative splicing of the microtubule-associated protein tau (MAPT) gene implicated in tauopathy. (A)MAPT gene is located on chromosome 17, position q21 and exons 2, 3 and 10 are alternatively spliced producing six tau isoforms. Exon 2 (blue) and 3 (green) encode for amino acid inserts in the N-terminal projection domain; whilst, exon 10 encodes for amino acids at the R2 repeat (red) at the C-terminal microtubule binding domain. (B) Equal ratio between 3 and 4R carboxyl repeats in the healthy adult brain which is skewed in primary tauopathies to producing more of either 3R repeat, as observed in Pick’s Disease (PiD), or 4R repeat, as observed in Corticobasal Degeneration (CBD) and Progressive Supranuclear Palsy (PSP). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Intracellular tau-mediated neurotoxicity in tauopathy. (A) Normal physiological function of tau. Tau proteins stabilise the microtubule via the C-terminal binding domain, which regulates microtubule dynamics. Tau proteins can prevent or reduce axonal transport (cargo) by acting as obstacles, halting anterograde cargo transport via kinesin or retrograde transport via dyenein. Tau binding is regulated by a phosphorylation/dephosphorylation equilibrium mediated by kinases and phosphatases, respectively. Tau unbinding via kinase regulated phosphorylation (pTau) allows for changes in microtubule dynamics, aiding in anterograde and retrograde axonal transport mediated by kinesin and dyenein motor proteins. (B) Tau-mediated neurotoxicity. In tauopathies, a disequilibrium favouring the hyperphosphorylation of tau, mediated by the hyperactivity of kinases and disregulation of phosphatases, leads to excessive accumulation of tau in the cytosolic space. Free tau is able to self-aggregate into tau oligomers via protein-to-protein binding domain interactions, causing synaptic dysfunction and neurotoxicity during early tauopathy. Additionally, tau oligomers can form paired helical filaments (PHFs) that can subsequently form neurofibrillary tangles (NFTs), which lead to synaptic dysfunction, neurotoxicity and cell death, predominantly during later stages of tauopathy.

Fig. 3

Mechanism for tau secretion in tauopathy. Tau aggregation into oligomers as a result of hyperphosphorylation leads to secretion of tau into the extracellular space by multiple secretory pathways. (1) Free cytosolic tau can be packaged into exosome vesicles within MVBs for secretion through the plasma membrane. (2) Tau can be packaged and secreted into the extracellular space via larger vesicles known as ectosomes that form at the plasma membrane and can be taken up by neighbouring cells via endocytosis. (3) Free tau can be released into the extracellular space in a vesicle free form after being packaged into endo-lysosomes and released at the plasma membrane. (4) Tau localised to the Golgi apparatus can be trafficked and packaged into endo-lysosomes before release at the plasma membrane. (5) Tau can be secreted directly through the plasma membrane by binding to PI(4,5)P2 on the cytosolic side of the membrane, altering membrane integrity and being captured by HSPGs on the extracellular side before secretion. (6) A direct transfer of tau from the secreting cell to the neighbouring cell can occur via tunnelling nanotubules connecting the cytoplasm of the two cells, bypassing the extracellular space. Tau released within the extracellular space can be taken up by recipient neighbouring cells.

Fig. 4

An overview of the prion-like propagation and internalisation of tau. Aggregated tau can be secreted from the pre-synaptic terminal of a damaged neuron into the extracellular space by mechanisms of secretion shown in Fig. 3. Once in the extracellular space, tau can be internalised by nearby reactive astrocytes, but, bulk internalisation may result in toxicity and consequent secretion of tau to the neighbouring neuronal environment possibly via the exosomal-dependant pathway. Reactive microglia also internalise tau via competing with CX3CL1 for binding and uptake through the CX3CR1 channel for degradation; however, similar to what can occur with Aβ in astrocytes, abundant tau internalisation could be toxic to the cell, leading to the secretion of tau from microglia via exosomes. Both vesicle bound and free tau can then be internalised by the dendrites of nearby healthy neurons via endocytosis of the protein or by the binding and uptake through muscarinic receptor M1 and M3 or by LRP1 receptors. Internalised tau can then ‘seed’ existing tau structures, causing conformational changes and leading to both NFT formation and the production of more tau oligomers which can, in turn, be secreted and propagated in a prion-like manner. In this manner, tau pathology can spread throughout the brain in tauopathies. Secretion is denoted by arrows whilst internalisation is represented by dashed arrows.