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. 2019 Apr 25;12:107. doi: 10.3389/fnmol.2019.00107

Spreading of α-Synuclein and Tau: A Systematic Comparison of the Mechanisms Involved

Eftychia Vasili 1, Antonio Dominguez-Meijide 1, Tiago Fleming Outeiro 1,2,3,*
PMCID: PMC6494944  PMID: 31105524

Abstract

Alzheimer's disease (AD) and Parkinson's disease (PD) are age-associated neurodegenerative disorders characterized by the misfolding and aggregation of alpha-synuclein (aSyn) and tau, respectively. The coexistence of aSyn and tau aggregates suggests a strong overlap between tauopathies and synucleinopathies. Interestingly, misfolded forms of aSyn and tau can propagate from cell to cell, and throughout the brain, thereby templating the misfolding of native forms of the proteins. The exact mechanisms involved in the propagation of the two proteins show similarities, and are reminiscent of the spreading characteristic of prion diseases. Recently, several models were developed to study the spreading of aSyn and tau. Here, we discuss the mechanisms involved, the similarities and differences between the spreading of the two proteins and that of the prion protein, and the different cell and animal models used for studying these processes. Ultimately, a deeper understanding of the molecular mechanisms involved may lead to the identification of novel targets for therapeutic intervention in a variety of devastating neurodegenerative diseases.

Keywords: alpha-synuclein, Parkinson's disease, tau, Alzheimer's disease, spreading

Introduction

Alzheimer's disease (AD) and Parkinson's disease (PD) are progressive, age-associated neurodegenerative disorders. Recent epidemiological studies revealed that around 50 million people worldwide are living with AD, and more than 10 million people above 60 years old with PD, respectively (Karlawish et al., 2017; Tysnes and Storstein, 2017). The prevalence of both diseases is increased in the highest age groups and the number will escalate rapidly the coming years (Karlawish et al., 2017; Tysnes and Storstein, 2017). While the clinical features are quite distinct between the two diseases, at the molecular level they are characterized by the misfolding, aggregation, and deposition of proteins in characteristic types of inclusions (Brion et al., 1985; Kosik et al., 1986; Iwai et al., 1995; Spillantini et al., 1997). Accumulation of aggregated tau is a hallmark of AD and related tauopathies and the accumulation of alpha-synuclein (aSyn) aggregates is the hallmark of PD and related synucleinopathies (Brion et al., 1985, 1986; Kosik et al., 1986; Wood et al., 1986; Wischik et al., 1988; Spillantini et al., 1997; Baba et al., 1998; Bayer et al., 1999). aSyn and tau are abundant brain proteins, both known as intrinsically disordered proteins (IDPs) with prion-like properties, as they can misfold, seed, and spread the misfolded conformation to normal monomeric forms of each protein (Uversky and Fink, 2004; Eliezer, 2009; Bartels et al., 2010; Wu and Baum, 2010; Coelho-Cerqueira et al., 2013).

Different strains of aSyn and tau display different cell binding and penetration properties, resulting in transmission of pathology between cells (Clavaguera et al., 2009; Guo and Lee, 2011; Hansen et al., 2011; Angot et al., 2012; Kfoury et al., 2012; Masuda-Suzukake et al., 2013; Wu et al., 2013; Recasens and Dehay, 2014; Sanders et al., 2014; Grozdanov and Danzer, 2018). It is currently thought that distinct protein conformations account for differences in seeding potency. Interestingly, several studies revealed the accumulation of abnormal tau aggregates in numerous cases of aSyn deposition, and vice versa (Brion et al., 1985; Kosik et al., 1986). The coexistence of aSyn and tau aggregates suggests a strong cross-talk between tauopathies and synucleinopathies, and raises the hypothesis that cross-seeding might take place, thereby contributing to disease progression (Kosik et al., 1986; Spillantini et al., 1997; Cabrales Fontela et al., 2017). Furthermore, the interaction between aSyn and tau appear to promote the oligomerization and solubility of each other in vitro and in vivo, thereby disrupting cytoskeletal organization, impairing axonal transport, and compromising synaptic organization (Masliah et al., 2001; Giasson et al., 2003; Kotzbauer et al., 2004; Bellani et al., 2010; Cabrales Fontela et al., 2017; Sotiropoulos et al., 2017; Biswas and Kalil, 2018; Ordonez et al., 2018; Prots et al., 2018; Tuerde et al., 2018; Yuan et al., 2018). However, the exact molecular mechanisms involved in the cross-talk between the two proteins, and in the propagation of pathology, are still obscure. Here, we discuss the current knowledge about the mechanisms involved in transmission of both proteins, focusing on similarities and differences between the different spreading mechanisms.

aSyn Structure and Function

Alpha-synuclein (aSyn) is a 14.5 kDa acidic protein of 140 amino acid residues, encoded by the SNCA gene (Chen et al., 1995), and is strongly implicated in PD. aSyn belongs to the synuclein family, together with beta- and gamma-synuclein.

aSyn was first isolated from the synaptic vesicles and nuclei of the electric organ of Torpedo californica (Maroteaux et al., 1988). In 1997, aSyn was identified as the major protein component of Lewy bodies (LBs) and Lewy neurites (LNs), the pathognomonic deposits in PD (Spillantini et al., 1997). In the same year, the first point mutation in the SNCA gene was associated with autosomal-dominant forms of PD, demonstrating the role of genetics in the disease (Polymeropoulos et al., 1997). Furthermore, the identification of families with duplications and triplications of the SNCA locus confirmed that increased levels of aSyn can cause disease (Singleton et al., 2003). These findings, along with a plethora of in vitro and in vivo studies, suggest that aSyn is a central player in a group of neurodegenerative disorders known as synucleinopathies.

aSyn is classified as an intrinsically disordered protein (IDP) as it lacks defined secondary structure (Uversky, 2003, 2011a,b; Bernado et al., 2005; Breydo et al., 2012). Although the precise physiological function of aSyn is still unclear, several studies suggest that aSyn is involved in the regulation of synaptic membrane processes and in neurotransmitter release through interactions with members of the SNARE family (Tsigelny et al., 2012; Bellucci et al., 2016). Surprisingly, studies in aSyn knockout mice revealed that aSyn is not essential for synapse formation and cell survival (Bisaglia et al., 2009).

The primary sequence of aSyn can be divided in three distinct domains: the amino-terminal domain (N-terminal, residues 1–60), the central domain (residues 61–95) and the carboxy-terminal domain (C-terminal domain, residues 96–140). The N-terminal domain includes four repeats of the 11 amino acid alpha-helical lipid-binding motif (KTKEGV) (Figure 1Ai, R1–4), enabling the formation of amphipathic α-helical structures upon interaction with lipid membranes (Jao et al., 2004, 2008; Georgieva et al., 2008). The lipid composition of membranes is critical for aSyn binding. aSyn specifically prefers the binding in membranes characterized by high concentrations in cholesterol and sphingolipids, known also as lipid rafts. It seems that lipid rafts serve as a platform, which promotes aSyn binding and oligomerization (Davidson et al., 1998; Jo et al., 2000; Fortin et al., 2004; Zabrocki et al., 2008; Middleton and Rhoades, 2010; Fabelo et al., 2011; Hellstrand et al., 2013).

Figure 1.

Figure 1

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Schematic illustration of aSyn and tau proteins. (A) aSyn is encoded by the SNCA gene. The primary sequence of aSyn can be divided in three distinct domains: the amino-terminal domain (N-terminal, residues 1–60), the central domain also known as NAC domain (residues 61–95), and the carboxy-terminal domain (C-terminal domain, residues 96–140). The N-terminal domain includes four repeats (R1–R4) of the 11 amino acid alpha-helical lipid-binding motif (KTKEGV). This region has propensity to form amphipathic α-helical structures upon interacting with lipid membranes. The NAC domain (non-amyloid-β component), contains three additional repeats (R5–R7) of the lipid-binding motif, is enriched in hydrophobic residues, leading to the formation of cylindrical β-sheets and amyloid-β fibrils. Both the N-terminal and NAC domain are characterized part of the membrane binding domain. The C-terminal domain is rich in acidic residues (15 acidic amino acids: 10 Glu and 5 Asp residues) and lacks defined secondary structure. (B) Tau is encoded by the MAPT gene. Alternative splicing of the MAPT gene results in six isoforms known as 2N/4R, 1N/4R, 0N/4R, 2N/3R, 1N/3R, and 0N/3R, depending on the presence or absence of exon 10 (4R or 3R) and on the numbers of amino-terminal inserts (0N, 1N, and 2N) encoded by exons 2 and 3. The primary sequence of the full-length human tau isoform can be divided in the N-terminal domain also known as projection domain, the central domain which is the microtubule binding domain (MTBD) and the C-terminal tail. The N-terminal consists of the acidic part encoded by exons 2 and 3 (E2-3) called inserts 1 and 2 (N1-2), followed by the proline-rich region (PRR). The MTBD in the longest isoform contains four repeats (R1-4). The region with the strongest propensity for microtubule polymerization is the oligopeptide “KVQIINKK” (residues 274–281), located in the sub-region between the R1–R2 repeats (red box). The C-terminal tail is enriched in positively charged residues. Notably, the region with the strongest propensity for microtubule binding is located in the sub-region between the R1–R2 repeats and, more specifically, is the oligopeptide “KVQIINKK” (residues 274–281), which is included only in the 4R tau isoform, providing a stronger binding affinity when compared to the 3R isoforms (Brandt and Lee, 1993; Goode and Feinstein, 1994; Sergeant et al., 2005).

Importantly, all the known mutations associated with familial forms of PD are clustered within the N-terminal region of aSyn (Polymeropoulos et al., 1997; Kruger et al., 1998; Zarranz et al., 2004; Appel-Cresswell et al., 2013; Lesage et al., 2013; Proukakis et al., 2013; Pasanen et al., 2014), reinforcing the hypothesis that changes in the lipid binding domain may be linked to aSyn pathology. Interestingly, aSyn was reported to be acetylated at the N-terminus in cells, an essential modification that protects its native conformation against pathological aggregation (Iyer et al., 2016; Bu et al., 2017). The central domain, also known as NAC domain (non-amyloid-β component) (Figure 1Ai), is enriched in hydrophobic residues and is involved in the pathologic aggregation of the protein due to conformational changes (El-Agnaf et al., 1998; Giasson et al., 2001; Bellucci et al., 2012). Interestingly, one phosphorylation site is present in the NAC domain—the S87 residue. S87 phosphorylation is increased in synucleinopathies, leading to inhibition of aSyn oligomerization which influences synuclein-membrane interactions (Paleologou et al., 2010). The carboxy-terminal domain (C-terminal domain) is characterized by a non-defined structure (Bisaglia et al., 2009) and incorporates most of the posttranslational modification sites (PTMs), including the most common phosphorylation at S129 (Fujiwara et al., 2002; Oueslati, 2016). The importance of phosphorylation is emphasized by a study showing that in DLB brains, approximately 90% of insoluble aSyn is phosphorylated at S129, compared with only 4% in soluble cytosolic aSyn (Anderson et al., 2006). This suggests the implication of phosphorylation in the aggregation propensity. These PTMs may act by modulating the structure, the physiological functions and the toxicity of aSyn. Furthermore, they can modulate protein-protein interactions, interaction with metal ions (Paik et al., 1999; Brown, 2007; Bisaglia et al., 2009), including Ca2+ binding (Nielsen et al., 2001), polyamine complexes binding, modulation of phospholipid-binding (Paleologou et al., 2008; Visanji et al., 2011), affecting the aggregation propensity of the protein. Moreover, the region plays a protective role against aggregation, due to the presence of all the five proline (Pro) residues of the protein (Meuvis et al., 2010). Changes in the charge or the hydrophobicity by residue substitution as well as deletion of the C-terminal lead to accelerated aggregation of aSyn in vitro (Hoyer et al., 2004). As mentioned above, aSyn has the ability to bind to acidic membranes. This binding is mediated by the amphipathic α-helix in the N-terminal domain. Under physiological conditions aSyn exists in a dynamic equilibrium between the unfolded cytosolic and the membrane–bound state (Burre et al., 2014). In contrast, under pathological conditions, aSyn adopts a β-sheet–rich amyloid conformation, which leads to the fibril formation and subsequently aSyn deposition into LBs (Pineda and Burre, 2017). Importantly, the α-helical part is responsible for the formation of the different types of oligomers, the species currently considered to be most toxic. However, the exact nature of those toxic species remains unknown, and is still unclear whether aggregation initiates from its lipid-bound part or from the unstructured cytosolic protein (Trexler and Rhoades, 2012; Chen et al., 2015; Ghosh et al., 2015; Gallea et al., 2018).

Tau Structure and Function

Tau was first discovered associated with microtubules, together with other microtubule-associated proteins (Weingarten et al., 1975; Kolarova et al., 2012). For this reason, it was included in the family of microtubule-associated proteins (MAPs). There are six different isoforms of tau in the central nervous system, generated from the MAPT gene, as a result of alternative splicing. These isoforms range from 352 to 441 amino acids (Neve et al., 1986). Each of the six tau isoforms differs in their primary structure due to the content of three (3R) or four repeats (4R) of the microtubule binding domains in the C-terminal region, in combination with the presence or absence of one (N1) or two (N2) amino acid inserts in the N-terminal part of the protein. The six isoforms are known as 0N/3R (352 residues, 60 kDa), 1N/3R (381 residues, 64 kDa), 2N/3R (410 residues, 69 kDa), 0N/4R (383 residues, 64 kDa), 1N/4R (412 residues, 69 kDa), and 2N/4R (441 residues, 74 kDa) (Figure 1 Bi), all showing higher apparent molecular masses than the predicted ones. Since the isoforms are differentially expressed in the brain during development, and stimulate microtubule assembly with different efficiencies, possibly possess particular physiological roles and implicated at different biological activities (Utton et al., 2001; Stanford et al., 2003). The shortest isoform is also known as “fetal tau isoform” because it is expressed also in the fetal brain, while all of them are detected in the human adult brain (Kosik et al., 1989; Stanford et al., 2003).

Importantly, in neurodegenerative diseases such as AD and PD, modified proportions of the different tau isoforms have been observed (Bre and Karsenti, 1990; Avila et al., 2004). Tau stabilizes the polymerization of microtubules through the three or four MTBR repeats in case of the longest isoform (Drubin and Kirschner, 1986; Maccioni et al., 1989). Under physiological conditions, in mature neurons, all tau protein is likely to be microtubule bound (Ackmann et al., 2000), and it is considered a dipole protein since the two ends of the protein have opposite charges (Sergeant et al., 2008).

The primary sequence of tau consists of the N-terminal domain, half of which is enriched in acidic residues, followed by a proline-rich region and the positively charged C-terminal tail.

Tau, like aSyn, is an intrinsically disordered protein, since it contains regions without defined secondary structure that are inserted between very short β-sheets and α-helices (Figure 1Bii). The protein can also undergo different types of PTMs like phosphorylation, ubiquitination, acetylation, glycation, methylation, truncation of the N- or C-terminal regions or nitration (Avila et al., 2004; Garcia-Sierra et al., 2008; Avila, 2009; Morris et al., 2015; Huang et al., 2016; Iqbal et al., 2016), that likely modulate its normal function and lead to pathological features. Notably, tau contains a high number of potential phosphorylation sites (80 serines/threonines and 5 tyrosines) (Grundke-Iqbal et al., 1986b; Bancher et al., 1989; Wang and Mandelkow, 2016). Most of these sites are located within the proline-rich region in close proximity to the MTBR domains and in the C-terminal tail (Figure 1Bi) (Buee et al., 2000; Sergeant et al., 2008). The phosphorylation state of the protein affects the secondary structure and, subsequently, regulates all the normal and abnormal functions like development, interaction with different protein partners such as microtubules, localization, aggregation, and spreading (Camero et al., 2014; Multhaup et al., 2015; Wang and Mandelkow, 2016). In principle, a normal and strictly controlled level of phosphorylation is required for the appropriate function of the protein, while the pathological state is characterized by hyperphosphorylation that leads the tau to lose its biological activity (Kopke et al., 1993).

The deposition of hyperphosphorylated tau in insoluble filaments in the brain is a pathological hallmark not only of AD but also of related neurodegenerative diseases, known as tauopathies, including frontotemporal dementias (FTD) like Pick's Disease and argyrophilic grain disease, progressive supranuclear palsy, and corticobasal degeneration (Grundke-Iqbal et al., 1986b). Major differences between tauopathies are the deposition of different isoforms of tau (Rademakers et al., 2004) and the occurrence of different structures of tau aggregates (Gerson et al., 2014; Dujardin et al., 2018). In AD, all the six-tau isoforms are hyperphosphorylated and aggregated into paired helical filaments (PHF) (Grundke-Iqbal et al., 1986a,b). In Pick's disease 3R isoforms are predominant, and the arrangement of tau is different than that in inclusions found in AD (Falcon et al., 2018). On the other hand, in the other tauopathies only the 4R isoform is present in the filaments (Goedert, 2015). In AD brains, the abnormally hyperphosphorylated tau is presented in the cytosol inhibiting the assembly of tubulin and disrupting microtubules. Furthermore, as a result of self-assembly is accumulated into neurofibrillary deposits in neurons and glial cells (Iqbal et al., 2010). In sporadic and familial FTD, several mutations have been identified in the tau gene. Some of these mutations are thought to disrupt the normal binding of tau to tubulin resulting in pathological deposits of hyperphosphorylated tau (Rademakers et al., 2004), or makes tau more vulnerable to self-aggregation (S422E, ΔK280, R5L, P301L, and R406W) (Haase et al., 2004; van Swieten et al., 2007; Mutreja et al., 2019). As with aSyn, it is believed that in a variety of tauopathies, the most toxic species are oligomeric, but the controversy is still not fully resolved. These oligomeric species are non-fibrillar, multimeric, soluble forms of the protein (Haase et al., 2004; Ghag et al., 2018). Examples of tauopathies where oligomers have been proposed as the toxic species include AD, corticobasal degeneration, Pick's disease, and progressive supranuclear palsy (Maeda et al., 2006; Patterson et al., 2011; Gerson et al., 2014).

Prions and Prion-like Spreading of Pathology

Prion diseases are infectious diseases that can be transmitted horizontally between individuals of the same or even different species (Costanzo and Zurzolo, 2013; Kizhakke et al., 2017). In these diseases, PrPC misfolds and converts into the pathogenic form PrPSc. PrPSc then acts as a template, converting endogenous PrPC into additional PrPSc, thereby spreading pathology in the brain (Brandner et al., 1996). Other proteins may manifest prion-like behavior. The prion-like behavior of amyloid-β has been broadly studied (Walker et al., 2016; Ruiz-Riquelme et al., 2018; Sarnataro, 2018). Alterations in amyloid-β conformation lead to aggregation and the formation of plaques, and it has been reported that amyloid-β can reach the brain form outside the CNS (Eisele et al., 2014).

The stable propagation of different misfolded protein conformations was established as a defining feature of the prion paradigm and of the prion-like spreading of pathology (Jucker and Walker, 2013). Importantly, both aSyn and tau appear to spread in a prion-like manner (Holmes et al., 2013). However, different structural features may affect the way they propagate. Each protein has a characteristic core that undergoes conformational changes and may lead to aggregation. In particular, these are the NAC region in aSyn and the MTBR (together with the final part of the poliproline region) domain in tau (El-Agnaf et al., 1998; Ackmann et al., 2000; Giasson et al., 2001). Differences in these regions may lead to differences in the aggregated species formed. Whether aSyn and tau spreading have an infectious nature like that of the prion protein remains unclear. In general, protein infectivity depends on several factors, such as irreversibility of misfolded protein assemblies, the efficiency by which precursor polypeptides are recruited into aggregates, the clearance of the aggregates, and the efficiency of the spreading of misfolded protein proteins (Brundin et al., 2010).

Spreading of aSyn Pathology

aSyn neuropathology typically progresses in a predictable manner throughout the brain. Post mortem analysis of human brains revealed progression of neuropathology in a series of stages (Braak et al., 2003a). Initially, the lesions start in the olfactory bulb, anterior olfactory nucleus, and dorsal motor nucleus of the vagus (Ordonez et al., 2018) in what is considered the first stage. During the second stage, pathology spreads to the lower raphe nuclei, the magnocellular portions of the reticular formation and the locus coeruleus (Prots et al., 2018). In the third stage, the pathology reaches the midbrain, affecting fundamentally the substantia nigra pars compacta (Braak et al., 2003a). Pathology spreads then to the cortex during the fourth stage. In this stage the mesocortex is affected whilst the neocortex is unaffected (Braak et al., 2003a,b). In the last two stages, pathology reaches the neocortex. Initially affecting the prefrontal neocortex and then moving to the premotor areas, the primary sensory areas and the primary motor field (Braak et al., 2003a).

aSyn can cross the blood-brain barrier (Peelaerts et al., 2015) and was shown to reach the central nervous system (CNS) after gastrointestinal administration (Holmqvist et al., 2014). It has been found in the choroid plexus, where it may be produced by the choroid cells that participate in its transport between the blood and cerebrospinal fluid (Bellani et al., 2010).

Additional studies showed the spreading of aSyn from diseased to healthy tissue. Several PD patients underwent embryonic neuronal cell transplantation developed the disease years after the surgery. The postmortem analysis of the tissue showed signs of PD, including the presence of LB and LN, in the grafted tissue. Interestingly, in these studies, the presence of cytosolic aSyn phosphorylated at S129 was also shown (Kordower et al., 2008; Li et al., 2008).

These studies, together with the Braak staging hypothesis, were considered strong evidence in favor of the prion-like spreading of aSyn pathology in the brain (Olanow and Prusiner, 2009).

Following these findings, several new studies revealed that aSyn can propagate from host to grafted tissue (Desplats et al., 2009; Angot et al., 2012; Reyes et al., 2014). A different set of studies showed how the administration of brain lysates from multiple system atrophy (MSA) patients into TgM83 mice brain leads to transmission in a way that is reminiscent of the transmission of the prion protein in chimpanzee brains in a model of Kuru (Gajdusek et al., 1966; Watts et al., 2013). This process was proposed to happen through cell-to-cell transmission following not only cell connectivity, and may reach parts of the CNS away from the injection site (Luk et al., 2012). Furthermore, 9 months after the inoculation of pathological aSyn from sarkosyl-insoluble fractions from cortical brain tissue from MSA patients, aSyn aggregates were found in the side contralateral to the administration (Bernis et al., 2015). Interestingly, in all these experiments human material leads to disease in different species. The transmission among different species is one of the main characteristics of prion proteins. Another argument in favor of the prion-like behavior of aSyn is that, under certain conditions, aSyn can assemble aberrantly forming prion strains (Guo et al., 2013; Peelaerts et al., 2015). When aSyn fibrils are inoculated in Wistar rats they act as seeds imprinting their intrinsic structures, turning monomeric aSyn into fibrils. When aSyn ribbons were injected, endogenous aSyn in Wistar rats acquired this specific conformation (Breydo et al., 2012). Furthermore, when two different strains of aSyn pre formed fibrils were inoculated in mice, endogenous aSyn acquired the structure of the strain inoculated (Peelaerts et al., 2015). Also, assemblies such as fibrils and ribbons can cross the blood-brain barrier and reach the CNS after intravenous injection (Uversky, 2011b).

Several mechanisms have been put forward to explain the spreading of aSyn between cells. These include membrane pores (Stockl et al., 2013), passive diffusion (Ahn et al., 2006; Grozdanov and Danzer, 2018), receptor mediated endocytosis (Mao et al., 2016), through exo- and endocytosis (Lee et al., 2005), exosomal transport (Emmanouilidou et al., 2010), tunneling nanotubes (Abounit et al., 2016a,b; Dieriks et al., 2017), and the possibility of transport through carrier proteins (Sung et al., 2001; Yang et al., 2017) (Figure 2).

Figure 2.

Figure 2

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Possible mechanisms associated with the cell-to-cell transmission of aSyn and tau. The release of tau and aSyn is thought to take place via different mechanisms: (1) aSyn oligomers may form pore-like structures that penetrate the plasma membrane. These structures may act as non-selective channels, leading to the release of aSyn. At the present moment, there is less evidence in support of such mechanism for tau; (2, 8) Direct penetration of the plasma membrane may lead to protein release through passive diffusion and, consequently, passive uptake from the extracellular space, a common mechanism for both proteins; (3) aSyn and tau monomers and oligomers may be released in exosomes/secretory vesicles; (4) transmission of aSyn and tau may also occur via tunneling nanotubes which are membrane bridges between the cells composed by F-actin; (5) another possibility is that aSyn interacts with a possible carrier protein, which mediates the transfer in the plasma membrane and subsequently the release—it is still not known if tau could be released in this manner; (6) the release of both proteins may also take place from dying cells and the uptake of aSyn and tau could be mediated by cell surface receptors; (7) Heparan sulfate proteoglycans (HSPGs) may facilitate the internalization of aSyn and tau. Both proteins (monomers or fibrils) bind HSPGs at the cell surface, and then get internalized; (9) both proteins may be taken up by endocytosis.

aSyn is present in extracellular fluids, as it has been found in human plasma and cerebrospinal fluid and in medium from cultured human M17 neuroblastoma cell line (El-Agnaf et al., 2003). The release of aSyn has also been shown in other cell lines such as SH-SY5Y cells, H4, MES cells, and in primary neurons (Lee et al., 2005; Danzer et al., 2011; Yamada and Iwatsubo, 2018). In these cells, aSyn is released through a calcium-dependent non-conventional pathway. Treatment with compounds that interfere with the normal function of endosomes result to significant changes in the extracellular levels of aSyn. Thus, the release pathway of aSyn is dependent on the integrity of the endosomal compartment (Emmanouilidou et al., 2010; Alvarez-Erviti et al., 2011; Emmanouilidou and Vekrellis, 2016). Release can also happen through exosomes. Exosomes are vesicles of <100 nm of diameter that facilitate intercellular communication transporting proteins or RNA (Jansen et al., 2017; Mutreja and Gamblin, 2017). They can be released through budding forming a small vesicle or formed inside the multivesicular body, which fuses then with the cell membrane releasing its vesicles into the extracellular space (Beaudoin and Grondin, 1991; Denzer et al., 2000; Rustom et al., 2004). Membrane carrier proteins like the secretory carrier membrane protein 5 can also participate in the release of aSyn through exosomes (Yang et al., 2017). These release processes can happen from either the cell soma or the synaptic button, as aSyn is also transmitted trans-synaptically (Danzer et al., 2011; Freundt et al., 2012; Yamada and Iwatsubo, 2018), in processes that may or may not require axon-dendrite contacts (Freundt et al., 2012). Interestingly, mutant forms of aSyn such as the H50Q and the G51D are more prone to be released via exosomes and other types of extracellular vesicles than the wild type protein (Falcon et al., 2018). In addition, aSyn can also reach the extracellular space, not only by active mechanisms, but also passively by leakage through damaged cell membranes or by cell impairments. This process can be exacerbated by aSyn itself, as its interactions and fibrillization may disrupt cell membrane integrity (Volles and Lansbury, 2002; Chaudhary et al., 2014).

Internalization can then happen through the aforementioned mechanisms. During pinocytosis, aSyn is internalized in a dynamin-dependent process which seems to be more relevant for monomeric than for aggregated aSyn (Hansen et al., 2011). Furthermore, the endocytic process of aSyn internalization is a dynamin-dependent process, but not clathrin-dependent (Uversky, 2011a).

Tunneling nanotubes are F-actin containing membranous bridges that connect the cytoplasm of remote cells, first described in PC12 cells (Abounit and Zurzolo, 2012). Fibrillar aSyn can spread from cell to cell in a prion-like way through tunneling nanotubes by mechanisms such as intercellular trafficking of lysosomes (Abounit et al., 2016a; Dieriks et al., 2017). This happens not only among neuronal cells, but also in pericytes and astrocytes (Dieriks et al., 2017; Rostami et al., 2017), and from one type of cell to another (Sun et al., 2012).

Changes in aggregation propensity like the ones mentioned above lead to changes in the internalization and clearance of aSyn (Lee et al., 2008).

It has been proposed that aSyn can cross the cell membrane through pore-like structures such as the β-barrel voltage-dependent anion channel (Hoogerheide et al., 2017). These pores can be formed by aSyn itself in its oligomeric form, as it crosses the cell membrane leading to the formation of octameric ring structures, being the mutant A53T more prone to do it (Ma et al., 2017). The formation of these pores by aSyn is related with its binding properties to membranes and lipid layers. The association with these membranes leads to changes in membrane conductance which result to changes in its pore activity formation (Tosatto et al., 2012). The association with membranes is dependent on the presence of the KTKEGV repeat motif (Jao et al., 2004). In fact, binding of aSyn to the cell membrane causes permeabilization of the cell membrane by decreasing the lipid order (Stockl et al., 2013). This process also facilitates passive diffusion of the protein. Passive diffusion is a mechanism that allows exclusively the internalization of monomers (Lee et al., 2008). It is noteworthy that changes in the amphipatic N-terminus lead to an altered binding of aSyn to membranes. This results in abnormal vesicle interactions and changes the conformation of the vesicles, affecting aSyn spreading (Taneva et al., 2012; Dettmer et al., 2017). Out of the three known membrane proteins described to interact with aSyn, only the LAG3 and PrPC mediate in its internalization through endocytosis (Chen et al., 2015; Mao et al., 2016; De Cecco and Legname, 2018). Activation of N-Methyl-D-Aspartate receptor (NMDAR) leads to the clathrin-mediated internalization of the receptor (Chen et al., 2017). Interestingly, activation of PrPc receptor by extracellular aSyn oligomers also leads to the phosphorylation of Fyn kinase activating the NMDAR receptor in a process that is independent of pore formation and impairs hippocampal long term potentiation leading to cognitive impairment (Diogenes et al., 2012; Chen et al., 2015).

Spreading of Tau Pathology

Tau also progresses in a predictable manner throughout the CNS. In AD, tau starts its propagation in the transentorhinal region and progresses through the hippocampus, cortex and the superior temporal gyrus, finally reaching the neocortex (Uversky, 2003; Braak et al., 2006). Nonetheless, particularly in FTD cases with Pick's disease type of tau pathology, atrophy progression starts in the frontal lobe and the hippocampus, then the temporal lobe and the insula, and finally pathology reaches areas of the parietal lobe (Broe et al., 2003; Gallea et al., 2018).

In mice, tau isoforms 2N4R, 2N3R, and 0N4R were found to readily and bidirectionally cross the blood-brain barrier (Ghosh et al., 2015).

Tau propagates trans-synaptically, mostly based on connectivity and not on proximity (Ahmed et al., 2014). This propagation happens mostly through afferent connections (Iba et al., 2015) and is mediated by trans-synaptic mechanisms (Dujardin et al., 2014), where transmission was proposed to take place through exosomes (Wang et al., 2017). Although propagation happens mainly through afferent connections, small tau species can be transported anterogradely and retrogradely in neurons (Wu et al., 2013). In P301S transgenic mice, tau pre-formed fibrils lead to templated misfolding of tau in a prion-like manner along neuronal connections (Stancu et al., 2015). When injected into the brain, aggregated P301S tau present in brain homogenates from P301S mice induces the spreading of filamentous tau pathology in ALZ17 mice (Clavaguera et al., 2009). Interestingly, the P301S mutant spreads at least five times faster than the wild type (WT) tau (Kundel et al., 2018).

In normal conditions, purified human tau does not form protein assemblies (Crowther et al., 1994). Polyanionic substances, especially glycosaminoglycans such as heparin or heparan sulfate proteoglicans (HSPGs), promote tau aggregation, thereby accelerating the formation of amyloid tau fibrils (Montejo de Garcini et al., 1986; Friedhoff et al., 1998). All six tau isoforms are able to aggregate even though, in vitro, the 4R isoforms are more prone to aggregation than the 3R isoforms (Zhong et al., 2012). Once the protein forms assemblies, these can act as seeds for the generation of new assemblies, even when they are applied extracellularly, spreading subsequently to other cells (Goedert and Spillantini, 2017).

Tau spreads from cell to cell through several different putative mechanisms, similar to those proposed for aSyn (Guo and Lee, 2011; Tardivel et al., 2016; Katsinelos et al., 2018; Polanco et al., 2018) (Figure 2). A mechanism that was proposed to be more frequent for tau than for aSyn, is the internalization of the protein via macropinocytosis (Lee et al., 2008; Holmes et al., 2013) (Figure 2). Macropinocytosis is an endocytic process driven by actin and involves the formation of the macropinosome in response to the direct actions of cargo/receptor molecules that coordinate the activity and recruitment of specific effector molecules, and subsequently fuse with degradative compartments of the cell (Kirkham and Parton, 2005; Kerr and Teasdale, 2009). Different types of HSPGs have been described to facilitate cellular internalization of aSyn and tau in vitro and in vivo and blocking their expression diminishes the internalization of tau and aSyn monomer and aggregates (Holmes et al., 2013; Gerson et al., 2014; Dujardin et al., 2018). Oligomers and short fibrils which bind to membranes can be internalized through receptor-independent mechanisms. On the other hand, monomers, long fibrils, or long filaments, are more dependent on receptor-mediated mechanisms (Wu et al., 2013). Extracellular tau can also affect the accumulation of endogenous tau in a way that is dependent on the tau isoform found in the extracellular space. In addition, it has been shown that oligomeric 0N4R tau induces the accumulation of endogenous tau to a small extent, while oligomeric 0N3R, 1N3R, and 1N4R tau do not stimulate accumulation of intracellular tau (Swanson et al., 2017).

Detachment of tau from microtubules, e.g., due to hyperphosphorylation, increases the levels of free intracellular protein, which can then cross the membrane through translocation mechanisms (Katsinelos et al., 2018). Certain extracellular forms of tau, especially soluble forms composed mostly of monomers and small oligomers, appear to be cytotoxic through muscarinic receptor activation, involving the tissue non-specific alkaline phosphatase (Sebastian-Serrano et al., 2018). Extracellular tau, mainly truncated forms, can also contribute to synaptic dysfunction (Brandt et al., 1995; Sebastian-Serrano et al., 2018). In fact, at least 75% of tau in the synapse of AD patients is C-terminally truncated, and can be released from cortical synapses and affect its physiological role (Sokolow et al., 2015). Interestingly, these truncated forms have been reported to undergo truncation from the C-terminus to inner regions and have been linked to the pathogenesis of AD (Basurto-Islas et al., 2008; Garcia-Sierra et al., 2008). So far, two major sites of truncation have been studied, especially truncation at residues E391 and D421. Interestingly, the truncation at D421 is not only found in AD brains, but also in Pick's disease brains, where C-terminal truncated tau has been proposed to be the main isoform found in exosomes (Mena et al., 1995; Gamblin et al., 2003; Basurto-Islas et al., 2008; Mondragon-Rodriguez et al., 2008; Kanmert et al., 2015). Furthermore, overexpression of the projection domain of tau suppresses neuronal growth factor-induced neurite formation, contributing to synaptic dysfunction (Brandt et al., 1995).

Cell Models for Studying the Spreading of aSyn and Tau

The mechanisms by which aSyn and tau spread through the central nervous system are of utmost importance to understand the progression of PD and AD, respectively. To study these mechanisms, several cell models of aSyn and tau spreading have been used in the last years.

Different cell lines have been used to study specific mechanisms underlying the spreading of aSyn and tau pathology. For instance, the mouse neuroblastoma N2a cell line has been extensively used to study cell-to-cell spreading through exosomes (Wang et al., 2017). Other cell lines, such as the HEK293, SH-SY5Y, and B103, or primary neuronal cultures, were also used to study exosomal-mediated release, but less frequently (Alvarez-Erviti et al., 2011; Polanco et al., 2016; Ngolab et al., 2017). The cell-to-cell transmission through tunneling nanotubes has been studied in the cathecolaminergic CAD cell line (Abounit et al., 2016a). The C17.2 neural precursor cell line was used to study macropinocytosis (Holmes et al., 2013) (Tables 1, 2).

Table 1.

Cell models used to study aSyn spreading.

Model Mutation Result References
SH-SY5Y None aSyn can be transferred from one cell to another via exosomes Alvarez-Erviti et al., 2011
N2a; primary hippocampal neuron; N2aprnp−/− None Prp facilitates the accumulation and spreading of aSyn aggregates in N2a cells and primary hippocampal neurons Aulic et al., 2017
HEK293T None Used to titer the viral vectors Azeredo da Silveira et al., 2009
Primary cortical neurons; primary astrocytes; human Lewy body incubation None Quantification of aSyn uptake in neurons and astrocytes Cavaliere et al., 2017
SH-SY5Y; primary cortical neurons; mouse cortical NSCs; aSyn expression using recombinant AdV None aSyn uptaken by cells; observed cell-to-cell propagation Desplats et al., 2009
SH-SY5Y None Cell to cell transfer in a 3D human neuron-like cell model Domert et al., 2016
SH-SY5Y; Tet-off system None aSyn is secreted through an endosomal pathway Emmanouilidou et al., 2010
HEK293; SH-SY5Y; SKMe15: N2A/SKMe15 coculture; CM with aSyn oligos None aSyn can transfer between cells and seed the assembly of soluble aSyn Hansen et al., 2011
Primary oligodendrocites; MN9D; Oli-neu; OLN93 A53T Oligodendrocytes, Oli-neu, and OLN-93 uptake aSyn. Uptake is inhibited when clathrin heavy chain is silenced Kisos et al., 2012
Primary cortical neurons; SH-SY5Y; KG1C; PC12 A30P; A53T Incorporated aSyn oligomers form cytoplasmic inclusions Konno et al., 2012
SH-SY5Y None aSyn is secreted through exocytosis Lee et al., 2005
SH-SY5Y A30P; A53T High level of expression Lo Bianco et al., 2002
Primary neurons; primary astrocytes; fibril administration None Transfer from neurons to astrocytes Loria et al., 2017
Primary neuron, microglial and astrocyte culture; COS-7; HeLa; HEK293FT; SH-SY5Y; PFF administration; PFF with biotin; aSyn-biotin PFF administration LAG3−/− Pathologic aSyn transmission and toxicity is initiated by binding to LAG3 and that neuron-to-neuron transmission of pathological aSyn involves the endocytosis of exogenous ASyn PFF by the engagement of LAG3 on neurons Mao et al., 2016
B103; human exosome incubation None Exosomes internalized by endocytosis Ngolab et al., 2017
HEK293; infected with MSA and PD samples A53T Samples from MSA patients could be transmitted to cultured HEK cells but not samples from PD Prusiner et al., 2015
OLN-93 None Capture of monomers, oligomers and fibrils Reyes et al., 2014
N2a; neuronal iPS; CM None Transfer from neuron to neuron Reyes et al., 2015
HEK293; PC12 None High level of expression Yamada et al., 2004
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CM, conditioned media; MSA, Multiple System Atrophy; PFF, Pre-formed fibril.

Table 2.

Cell models used to study tau spreading.

Model Mutation Result References
CAD; HeLa; h tau fibrils administration None Tau fibrils are internalized and appear inside tunneling nanotubes Abounit et al., 2016b
Rat primary neuronal cultures; V5-Tau-LV or eGFP-LVs treatment P301L Cell-to-cell transfer of WT V5-Tau protein via axonal transport from the primary neurons; transferred species mainly in a dephosphorylated state Dujardin et al., 2014
HEK293T; HEK-TREx-293; h tau transfection; sarkosyl insoluble tau and total brain lysate from TgP301S mice administration P301S Native Tau aggregates enter Cells through the same mechanism as recombinant Tau aggregates, consistent with macropinocytosis Falcon et al., 2015
QBI-293; human WT, P301L, T43, t40/deltaK280, T40/P301L, and T40/R406W transfection; myc-tau and K18 fibril administration P301L; deltaK280; R406W Spontaneous fibril uptake is mediated by endocytosis Guo and Lee, 2011
C17.2; HEK293; tau RD-CFP, tau RD-YFP, and FRET biosensor for tau; aSyn-488, Htt exon 1 (Q50) administration P301L; V337M Tau fibrils enter cells via macropinocytosis; HSPGs are receptors for cell uptake of tau and α-synuclein Holmes et al., 2013
Mice primary neuronal cultures; HEK293T; liposome transduction of tau seeds; treatment with tau, synuclein and Htt(Q50) seeds; tau RD-CFP, tau RD-YFP, and FRET biosensor tau cell line P301S Seeding with tau seeds; interaction with synuclein Holmes et al., 2014
HEK293; tau RD-CFP, tau RD-YFP, and FRET biosensor for tau deltaK280; P301L; V337M; I227P; I308P Repeat domain aggregates transfer between cells, induce aggregation and propagate misfolding between cells; transfer within cell medium Kfoury et al., 2012
M1C; NB2a/d1; pRcCMV and pcDNA/V5-DEST transfection None Tau exon 2 insert inhibits tau secretion Kim et al., 2010
Primary neuronal cultures; primary microglial cultures; primary astrocyte cultures; COS-7; HeLa; HEK293FT; SH-SY5Y; PFF administration; PFF with biotin; aSyn-biotin PFF administration LAG3 -/- Tau PFF do not bind LAG3 Mao et al., 2016
HEK293; HEK293T; tau RD-CFP, tau RD-YFP, and FRET biosensor tau cell line P301L Transfer of seeds through exosomes; P301L tau-containing exosome-like EVs carry tau seeds that are capable of inducing aggregation of endogenous tau after being taken up by recipient tau biosensor cells Polanco et al., 2016
Primary neuronal cultures; mCherry-CD9-10 and Dendra2-CD9-10 transfection; exosome administration P301L Exchange of exosomes by interconnected neurons Polanco et al., 2018
Primary neuronal cultures None Stimulation in release by neuronal activity; probably through a pre-synaptic mechanism rather than by extrusion of exosomes Pooler et al., 2013
HEK293; tau RD-YFP, aSyn-YFP, htt exon 1 (Q25)-YFP P301S Seeding dependent on beta-sheet structure; tau propagates different strains; propagates to naïve cells after lysate transduction Sanders et al., 2014
SH-SY5Y; h 3R1N, 4R1N, and HA-4R1N tau transfection; h APP-695 wild-type (WT), F690P, KM670/671NL, V717F, V717G, and APP-C99 transfection; h tau fibrils administration F690P (for APP) Overexpressed APP on the cell surface associates with tau fibrils and accelerates intracellular tau aggregation; transient expression of APP may increase the activity of cellular endocytosis and metabolism of APP Takahashi et al., 2015
CAD; V5-hTau1N4R, mCherry-tubulin and GFP-actin LV infection None Extracellular tau species activate the formation of TNTs; tau is transported through TNTs via actin Tardivel et al., 2016
N2A; GFP-Tau, RFP-Tau, GFP-flotillin deltaK280 Release of seeding prone tau through exosomes; mutants for FTDP more prone; synaptic contacts are required for exosome-mediated transmission of tau Wang et al., 2017
Mice primary neuronal cultures; HeLa; low MW aggregates administration MAPT−/− Tau aggregates are taken up in tau KO mice neurons; small tau aggregates internalized and anterogradely transported in neurons and non-neuronal cells Wu et al., 2013
Mice primary neuronal cultures; RD-P301S YFP inoculation P301L; MAPT−/−:GFP Transfer through cell medium Wu et al., 2016
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h, human; KO, Knockout; APP, Amyloid precursor protein; FTDP, Frontotemporal Dementia; TNT, Tunneling nanotube; WT, wild type; MW, molecular weight.

Animal Models for Studying the Spreading of aSyn and Tau

In recent years, animal models based in the administration of different forms of aSyn and tau in specific brain and peripheral areas have been used (Table 3). The use of animal models enables us to address specific aspects of the spreading of aSyn or tau pathology, in particular those related to neuronal connectivity, or to the spreading between different organs (Braak and Braak, 1991; Delacourte et al., 1999; Zaccai et al., 2008). For aSyn, both mice and rats have been extensively used (Hansen et al., 2011; Masuda-Suzukake et al., 2013; Holmqvist et al., 2014; Recasens and Dehay, 2014), while in the case of tau most studies employed mice (Dujardin et al., 2014).

Table 3.

Animal models used to study aSyn spreading.

Model Site of injection Material injected Mutation Result References
Sprague-Dawley rats Substantia nigra AAV2/6-haSyn, transplanted rat VM DAnergic neurons None Propagation from host tissue to transplanted dopaminergic neurons Angot et al., 2012
Mice: Prnp−/−; prnp+/+ Substantia nigra Recombinant aSyn fibrils None Spreading of aSyn may be facilitated by PrP Aulic et al., 2017
Wistar rats Substantia nigra AAV2/6-CMV:-aSyn, -S129A-aSyn, -S129D-aSyn, -A30P-aSyn, -A30P-S129A-aSyn, -A30P-S129A-aSyn S129A; S129D; A30P S129A leads to the formation of smaller aggregates, S129D to larger Azeredo da Silveira et al., 2009
Tg(SNCA)1Nbm/J Left striatum MSA and ILBD brain lysates inoculation Insoluble fraction of human cerebral cortices aSyn−/− Transmission of aggregates to the contralateral side 9 months after inoculation Bernis et al., 2015
Rats: Sprague-Dawley, Wistar, Lewis; mice: C57BL/6J, SAMP8, SAMR1 Callithrix jacchus Substantia nigra (rodents) AAV2/9-p.A53T-haSyn pAAV2-CMVie/hSyn-synA53T-WPRE-pA A53T Spreading to striatum and throughout the whole mesencephalon in rats 16 weeks after surgery. Absence of spreading for phosphor-aSyn in rats and marmosets Bourdenx et al., 2015
Sprague-Dawley rats Substantia nigra rAAV2/1-aSyn G2019S (LRRK2); h aSyn OX Neurodegeneration in the contralateral side Daher et al., 2015
Sprague-Dawley rats Substantia nigra rAAV6-aSyn-WPRE, rAAV6-aSyn+WRPE, or rAAV-CBA-mutant aSyn h aSyn OX Retrograde progression of neurodegeneration Decressac et al., 2012
(Thy1)-hαSYN transgenic mice Hippocampus Lentiviral GFP, stem cells, MCNSC cells h aSyn Transmission of aSyn from host to grafted NSCs; Inclusion body formation via cell-to-cell transmission of aSyn Desplats et al., 2009
Callithrix jacchus Substantia nigra rAAV2/5-CBA-aSyn A53T Presence of aggregates in the CP 1 year after transduction in the SN Eslamboli et al., 2007
(Thy1)-h[A30P]aSyn transgenic mice None None A30P Widespread presence of aSyn aggregates after 12 months Freichel et al., 2007
Sprague-Dawley rats; WT C57BL/6J mice Right cortex Recombinant aSyn monomers, oligomers and fibrils h aSyn aSyn can transfer between cells and seed the assembly of soluble aSyn Hansen et al., 2011
C57BL/6J mice; C57BL/6JOlaHsd mice Left vagus AAV2/6-aSyn, AAV2/6-GFP KO of SNCA gene; h aSyn OX Spreading from medulla oblongata to rostral brain regions Helwig et al., 2016
Sprague-Dawley rats Intestine wall of the stomach and duodenum PD brain lysate, recombinant aSyn monomers, oligomers and fibrils None Spreading from stomach and duodenum to CNS Holmqvist et al., 2014
BDF1 mice Striatum DLB brain lysate sarkosyl soluble/ insoluble fractions h aSyn OX Inoculation fractions of human LBD in mice leads to CNS pathology Jones et al., 2015
Sprague-Dawley rats Right substantia nigra rAAV-CBA-GFP, rAAV-CBA-aSyn, rAAV-CBA-μaSyn A53T Overexpression of wt or mutant aSyn induce a progressive neurodegenerative pathology in the nigrostriatal DA neurons Kirik et al., 2002
Callithrix jacchus Substantia nigra rAAV-CBA-aSyn, rAAV-CBA-μaSyn, rAAV-CBA-GFP h aSyn OX Spreading from medulla oblongata to rostral brain regions. Release do not enhance interneuronal hα-syn propagation Kirik et al., 2003
A53T aSyn tg mice; Clathrin silencing None None A53T Oligodendrocytes, Oli-neu and OLN-93 uptake aSyn. Uptake is inhibited by silencing the expression of clathrin heavy chain Kisos et al., 2012
Sprague-Dawley rats Substantia nigra AAV-pTR-UF12, AAV-GFP, and AAV-pSyn30 A30P Accumulation of aSyn in SN after 12 months; presence of Lewy-like neurites in the SN and the striatum Klein et al., 2002
Sprague-Dawley rats Substantia nigra AAV1/2-A53T, AAV1/2-GFP, AAV1/2-EV A53T Transmission to the striatum from the SN Koprich et al., 2010
Cynomolgus macaque Substantia nigra AAV1/2-A53T, AAV1/2-aSyn, AAV1/2-GFP, AAV1/2-WPRE-bGH-polyA A53T; scrambled A53T Age-dependent increase in the accumulation of A53T; higher levels and more widespread degeneration with A53T Koprich et al., 2016
F344 rats Striatum and ventral mesencephalon AAV6-aSyn, AAV6-GFP None Fetal DA neurons grafted into the striatum of 6-OHDA lesioned rats can retrogradely transfer h aSyn from the host into the graft Kordower et al., 2011
Rats Right substantia nigra VSV-G-A30P, VSV-G-A53T, VSV-G-HWT A30P; A53T; wt Overexpression of wt or mutated h aSyn leads to dopamine neuronal cell death in rodents not only in the site of injection Lo Bianco et al., 2002
TgM83 transgenic mice Somatosensory cortex and dorsal neostriatum M83 mice brain lysate and recombinant aSyn fibrils A53T; aSyn−/− Pathological aSyn propagated along major CNS pathways to regions far beyond injection sites Luk et al., 2012
Sprague-Dawley rats Above the right substantia nigra rAAV6-aSyn, rAAV6-GFP None Development of degenerative changes in the nigrostriatal axons and terminals and DA release impairments Lundblad et al., 2012
C57BL/6 mice; CD1 mice Striatum Recombinant aSyn fibrils A53T; LAG3 -/- Pathologic aSyn transmission and toxicity initiated by binding to LAG3, endocytosis of exogenous aSyn PFFs by the engagement of LAG3 on neurons Mao et al., 2016
C57BL/6J mice Substanstia nigra Recombinant aSyn monomers and fibrils None aSyn is deposited in neurons through a prion-like mechanism or by seed-dependent aggregation by crossing the species barrier Masuda-Suzukake et al., 2013
TgM83 transgenic mice Intracerebral inoculation M83 mice brain lysate A53T; aSyn−/− Data consistent with prion-like propagation of aSyn Mougenot et al., 2012
WT C57BL/6J × DBA/2F1 mice Hippocampus DLB exosomes None Exosomes may play a role in aSyn pathogenesis, possibly through the seeding of toxic forms of aSyn Ngolab et al., 2017
C57BL/6 mice Right substantia nigra rAAV2/7-haSyn A53T Progressive nigral dopaminergic neuron loss, presence of aSyn-rich inclusions in the surviving cell bodies Oliveras-Salva et al., 2013
Wistar rats Right substantia nigra and striatum A53T α-SYN rAAV2/7, recombinant aSyn monomers, oligomers and fibrils h aSyn OX aSyn crosses the blood brain barrier; propagation in a stain-dependent manner Peelaerts et al., 2015
TgM83 transgenic mice Right parietal lobe PD and MSA brain lysate, M83 mice brain lysate A53T Transmission of MSA prions requires Tg A53T aSyn mice. Unsuccessful transmit PD to TgM83+/– mice Prusiner et al., 2015
Mice: WT C57BL/6J; C57BI6Sv129; Macaca fascicularis Above the substantia nigra (mice) and motor striatum (monkeys) PD brain lysate aSyn−/− Whether injected into the striatum or the SNpc, LB-induced degeneration was detected earlier and more extensively at the level of striatal dopaminergic axon terminals rather than SNpc cell bodies. Recasens and Dehay, 2014
C57BL/6J mice; Sprague-Dawley rats Cortex Recombinant aSyn monomers, oligomers and fibrils h aSyn OX Transfer from host brain to grafted oligodendrocytes; oligodendrocytes take up recombinant aSyn monomers and oligomers Reyes et al., 2014
(Thy1)-h[A30P]aSyn transgenic mice None None A30P Nutritional factors can have a significant impact on α-synucleinopathy Rotermund et al., 2014
Sprague-Dawley rats Intravagal AAV2/6-aSyn h aSyn OX Transfer to medulla oblongata from higher brain regions Rusconi et al., 2018
Mice: M20+/+; BL6C3HF1 Lateral to the lateral ventricles Recombinant Δ71-82 and full lenght aSyn fibrils h aSyn OX Non-amyloidogenic Δ71-82 aSyn induce pathology. Amyloidogenic h aSyn shows limited induction of neuronal aSyn inclusions Sacino et al., 2013
Mice: M83+/+; M83+/−−; M20+/+; C3H/C57BL6 n Biceps femoris Recombinant Δ71-82 and full lenght aSyn fibrils A53T; h aSyn OX Hindlimb intramuscular injection of fibrillar aSyn lead to CNS inclusion pathology Sacino et al., 2014b
Thy-aSyn mice Oral administration PD gut microbiota aSyn OX Microbiota are required for the motor and GI dysfunction, postnatal gut-brain signaling by microbial molecules impact neuroinflammation and αSyn aggregation Sampson et al., 2016
(Thy1)-h[A30P]aSyn transgenic mice None None A30P Pathological aSyn species can impair synaptic plasticity Schell et al., 2012
Callithrix jacchus Caudate nucleus and putamen Recombinant human and mouse aSyn monomers and fibrils None Retrograde progression of neurodegeneration Shimozawa et al., 2017
C57BL/6 Substantia nigra rAAV GFP and rAAV aSym h aSyn OX Slow disease progression that mimics human disease and allows for earlier points of characterization and/or intervention St Martin et al., 2007
Wistar rats Left substantia nigra AVV2: -aSyn, A56P-aSyn, -A30P, -A30P/A56P/A76P, -EGFP A30P; A56P; A30P/A56P/A76P Fibrillar and prefibrillar aSyn variants secreted from rat primary cortical neurons Taschenberger et al., 2012
C57BL/6J × CBA/ca hybrid mice None None Truncated 120 aa h aSyn120 under the control of the TH promoter led to the formation of pathological inclusions in SN and OB Tofaris et al., 2006
Rats; mice Substantia nigra AAV: -aSyn, -EGFP Truncated 120 aa Development of inclusions in axons Tozzi et al., 2016
Sprague-Dawley rats Right substantia nigra rAAV5-αsynΔ110+rAAV5-GFP, rAAV5-αsynFL+rAAV5-GFP, or rAAV5-αsynFL+rAAV5-αsynΔ110 Truncated 110 aa Mixture of truncated and full length, lead to increased accumulation and pathological aSyn in the striatum Ulusoy et al., 2010
Sprague-Dawley rats Left vagus rAAV6: -aSyn, -GFP h aSyn OX Spreading from medulla oblongata to rostral brain regions Ulusoy et al., 2013
Sprague-Dawley rats Left vagus rAAV6: -aSyn, -GFP h aSyn OX Spreading from medulla oblongata to rostral brain regions Ulusoy et al., 2015
Sprague-Dawley rats Substantia nigra AAV: -aSyn, -EGFP None DMV nerve has a role in the transmission of aSyn from the brain to peripheral tissues Ulusoy et al., 2017
Wistar rats Substantia nigra rAAV: 2/1, 2/2, 2/5, 2/6.2, 2/7, 2/8, and 2/9 eGFP None High widespread transgene expression Van der Perren et al., 2011
TgM83 transgenic mice Right parietal lobe MSA brain lysate, M83 mice brain lysates A53T; GFAP-Luc Lethality upon transmission to animals and similar transmission to that of kuru, CJD, and related diseases Watts et al., 2013
Sprague-Dawley rats Left substantia nigra rAAV-aSyn, rAAV-EGFP None Progressive dopaminergic cell loss and aggregation Yamada et al., 2004
Mice; Macaca fascicularis Substantia nigra (rodents and monkeys) Lentiviral A53T and GFP A53T Age-dependent increase in the accumulation of A53T; higher levels of degeneration in monkeys than in mice Yang et al., 2015
1K and 3K mice None None E35K, 346K, 361K 3K mutation causes shift from cytosolic to membrane associated aSyn Nuber et al., 2018
M83, M47, and haSyn mice Hippocampus and cortex Recombinant human, mouse A53T and E36K aSyn fibrils A53T, E46K Spreading of inclusion pathology only in M83 mice after 4 months Sacino et al., 2014a
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OX, overexpressing; CP, Cerebral Palsy.

Non-human primates have already been used to study the spreading of aSyn pathology (Kirik et al., 2003; Eslamboli et al., 2007; Shimozawa et al., 2017), but have not been reported thus far for the study of tau spreading. Interestingly, a lamprey model has been used to study the effects of several tau mutations in the progression of neurodegeneration (Lee et al., 2009).

Transgenic mice expressing mutant forms of aSyn, such as A53T and A30P, have also been used, and are proving useful for studying other synucleinopathies including MSA (Giasson et al., 2002; Prusiner et al., 2015). For tau, the rTg4510 mouse line, harboring the P301L mutation, has been widely used (Barghorn et al., 2000).

Additionally, injections of viral vectors have been also extensively used to induce aSyn and tau overexpression. In the case of aSyn, several studies reported the mimicking of relevant PD features, the progressive nature, and the spreading of pathology, in mice, rats, and non-human primates (Kirik et al., 2002, 2003; St Martin et al., 2007; Low and Aebischer, 2012). In the case of tau there are also models based on the use of viral vectors (Klein et al., 2008), including models for the study of rapid tau propagation (Asai et al., 2015) (Tables 3, 4).

Table 4.

Animal models used to study tau spreading.

Animal model Site of injection Material injected Mutation Result References
C57BL/6J mice Left hippocampus Mice brain extract P301S Spreading through connectivity Ahmed et al., 2014
PS19 tau mice; microglial depletion Medial entorhinal cortex, dentate gyrus AAV2/6-SYN1, AAV2/6-SYN1-GFP, AAV2/6-GFP. Exosomes from microglial culture, exosomes from mouse brain lysates P301L Participation of microglia in the spreading of tau; mediation of exosomes Asai et al., 2015
Wistar rats Striatum lentiviral hTau46WT, hTauP301L and GFP P301L AT8 immunoreactivity extends from the CA1 (Cornus Ammonis area 1) to the cortex in rats injected with LV-hTau46WT, whereas it is restricted to the hippocampal formation in rats injected with LV-hTau46P301L, even 8 months p.i Caillierez et al., 2013
C57BL/6J mice; ALZ17 mice Hippocampus and overlying cerebral cortex Mice brain homogenate P301S Transmission of hyperphosphorylated tau in mice transgenic for human wt tau Clavaguera et al., 2009
ALZ17 mice; APP23 mice Hippocampus and overlying cerebral cortex AD, tangle only dementia, Pick's Disease, argyrophilic grain disease, progressive supranuclear palsy, and corticobasal degeneration human brain extracts P301S; h APP Self-propagation of tau inclusions independently of other pathological mechanisms Clavaguera et al., 2013
C57BL/6J mice Intraperitoneal P301S and WT mice brainstem homogenate P301S Tauopathies can be seeded in the brain by tau aggregates delivered peripherally Clavaguera et al., 2014
rTG tau EC mice None None P301L Spreading of the pathology to downstream connected neurons de Calignon et al., 2012
Wistar rats Striatum lentiviral V5-hTau46WT, hTau46WT, hTauP301L, and eGFP P301L Spreading of Tau throughout the brain 8 months after post-injection; transmission through connected areas; trans-synaptic transmission Dujardin et al., 2014
C57BL/6J mice Cortex FL-Tau-488 fibrils None Tau fibrils enter cells via macropinocytosis; HSPGs are receptors for cell uptake of tau and aSyn Holmes et al., 2013
B6C3 mice; C57BL/6J mice None None P301S Tau seeding activity detected at 1.5 months, before any changes in histopathology; hyperphosphorylated tau accumulation Holmes et al., 2014
PS19 tau mice Locus coeruleus Recombinant tau fibrils P301S The pattern of spreading did not match neurofibrillary tangles staging in h AD brains, developed tau pathology more rapidly after tau PFF injections into the LC. Iba et al., 2015
Lamprey Hindbrain WT htau23 and htau24 plasmids P301L; G272V; V337M; R406W All mutations accelerate progression Lee et al., 2009
Neuropsin-tTA-Tau None None P301L Spreading from the entorhinal cortex Liu et al., 2012
Tg tau P301L mice Hippocampus Recombinant tau fibrils P301L Single injection of tau PFFs in the hippocampus or frontal cortex of young tauP301L mice acts as a seed to induce spreading of tau pathology throughout the mouse brain; neuron loss in the hippocampus Peeraer et al., 2015
rTg4510 mice None None P301L Transfer of seeds through exosomes; P301L tau-containing exosome-like EVs carry tau seeds that are capable of inducing aggregation of endogenous tau after being taken up by recipient tau biosensor cells Polanco et al., 2016
B6C3 mice Hippocampus Mice brain homogenate P301S; h 4R1N Spreading from the left hippocampus after 5 weeks to the entorhinal cortex, retrospenial cortex and contralateral hippocampus Sanders et al., 2014
rTg4510 mice Cerebral cortex Recombinant tau short filaments P301L Tau aggregates taken up in tau KO mice neurons; tau aggregates internalized and anterogradely transported between brain cells Wu et al., 2013
rTg4510 mice; neuropsin-tTA-Tau Medial entorhinal cortex and hippocampus AAV5 CamKII.hM3Dq-mCherry, AAV9/CamKIIa.hChR2-mCherry, AAV9/CamKIIa.hChR2-mCherry P301L; h tau; KO Stimulation of release and spreading by increased neuronal activity Wu et al., 2016
JNPL3; Tg4510 mice Intraperitoneal Pan-tau Abs DA9, and DA31, PHF-tau CP13, and RZ3 antibodies; and 1 conformation-specific antibody MC1 P301L Tau detected in serum d'Abramo et al., 2016
mice JNPL3 Hippocampus AAV5-scFv-MC1, AAV5-eGFP P301L Diffusion to distant areas Vitale et al., 2018
P19 mice Right lateral ventricle Human antisense oligonucleotides P301S Decrease in human tau mRNA reverses tau seeding DeVos et al., 2017
SHR24, SHR72 rats Motor cortex Sarkosyl insoluble SHR72 and SHR24 brain homogenate Truncated aa 151-391 3R and 4R tau Spreading only of the SHR72 4R tau variant Levarska et al., 2013
SHR72 rats Hippocampus AD brain insoluble fraction, human brain extract Truncated aa 151-391 4R tau Exogenous human AD tau was able to spread from the area of injection and induce tau pathology Smolek et al., 2019
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Conclusions

Tau and aSyn pathologies spread in a manner that is reminiscent of the process of prion spreading in prion diseases, whereby misfolded forms of the proteins can act as templates and induce the misfolding of normally structured proteins. The altered proteins can spread from cell to cell throughout the CNS, and possibly also between different organs through neuronal connections.

In contrast to prion diseases, in AD and PD there is still no definitive evidence for horizontal transmission of tau or aSyn pathologies, as these proteins have not been shown to be infectious. Additionally, the spreading of pathology in synucleinopathies and tauopathies seems to be slower than that observed in prion diseases, but the reason for this is still unknown (Yekhlef et al., 2003; Peden et al., 2004; Schofield et al., 2005; Desplats et al., 2009; Angot et al., 2012; Reyes et al., 2014; Mabbott, 2017).

The putative mechanisms involved in the spreading of both tau and aSyn are thought to be similar. One difference is that tau appears to have greater propensity to be internalized through macropinocytosis. Another difference is that, thus far, no putative direct receptors have been involved in mediating tau internalization, whereas for aSyn several putative “receptors” have been reported.

From an anatomical point of view, aSyn and tau appear to spread from and to different locations, in patterns that are relatively predictable (McCann et al., 2016; Hoenig et al., 2018; Schwarz et al., 2018).

In conclusion, through the use of different model systems, it is becoming evident that the spreading of aSyn and tau pathologies share similar mechanisms, and there is hope that a deeper understanding of those mechanisms may lead to the identification of novel targets for therapeutic intervention in various neurodegenerative diseases.

Author Contributions

EV and AD-M reviewed the literature and contributed equally to the design and writing of the manuscript. TO reviewed the final manuscript.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Footnotes

Funding. TO is supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB) and by a grant from Fundación La Marato de TV3 (Ref. 20144330). This work has received support from the EU/EFPIA/Innovative Medicines Initiative [2] Joint Undertaking (IMPRIND grant n° 116060). AD-M is supported by a postdoctoral fellowship from the Galician Government (Programa de axuda á etapa posdoutoral, XUGA, GAIN, ED481B 2017/053).

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