In fact, tau oligomers might disrupt microtubule stability and trafficking, thus affecting organelle distribution
Evidence shows that tau aggregates colocalize with dextran and HeLa cells, hinting that internalized aggregates are transported in endosomal vesicles and passed through the endosomal pathway to lysosomes (Wu et al., 2013)
Compared to non-demented controls, AD brains exhibit up to 50% of neuronal loss in the cortex, exceeding the number of NFTs (Gómez-Isla et al., 1997)
Recently, more evidence implies that the secretion of tau occurs through unconventional cellular pathways via vesicles known as exosomes (Saman et al., 2012) and ectosomes (Dujardin et al., 2014a)
Significantly, evidence suggests that tau secretion is partly mediated by ectosomal vesicles and that pathological tau accumulation in cells leads to a deviation toward tau secretion by exosomal vesicles (Dujardin et al., 2014a)
These share a common histopathological hallmark known as neurofibrillary tangles (NFTs) that consist of an accumulation of fibrillar tau deposits initially produced from tau protein aggregation (Ballatore et al., 2007)
Additionally, studies have discovered that aggregated tau inhibits fast axonal transport in the anterograde direction at all physiological tau levels, whereas tau monomers have had no effect in either direction (LaPointe et al., 2009; Morfini et al., 2009)
A recent study showed that neuronal networks facilitate cell-to-cell transfer of tau via synapses; using a microfluidic device they demonstrated that decreasing synaptic connections weakens tau transfer and the subsequent aggregation on the acceptor cell (Calafate et al., 2015)
Hence, tau APFs may play a significant role in tauopathies by linking pore formation to cell death
As these granular tau oligomers fuse together, they form tau fibrils, which ultimately form NFTs (Takashima, 2013)
While evidence indicates that these deposits are not toxic, many studies suggest that the tau oligomer, an intermediate entity, is likely responsible for disease onset
These tau oligomers potentiate neuronal damage, leading to neurodegeneration and traumatic brain injury (Hawkins et al., 2013; Gerson et al., 2014a, 2016; Sengupta et al., 2015). Moreover, they have been implicated in synaptic loss as shown in studies of wild-type human tau transgenic mice (Spires et al., 2006; Berger et al., 2007; Clavaguera et al., 2013)
These studies demonstrate that tau oligomers may be the toxic entities responsible for neurodegeneration in tauopathies (Ward et al., 2012
When the oligomer lengthens, it adapts a beta-sheet structure and transforms into a detergent-insoluble aggregate with granular appearance under Atomic Force Microscopy (AFM)
The onset of clinical symptoms in AD and PSP brains correlate with elevated levels of tau oligomer (Maeda et al., 2006, 2007; Patterson et al., 2011; Lasagna-Reeves et al., 2012b; Gerson et al., 2014a)
When tau oligomers, rather than tau monomers or fibrils, are injected into the brain of wild-type mice, cognitive, synaptic, and mitochondrial abnormalities follow (Lasagna- Reeves et al., 2011; Castillo-Carranza et al., 2014b)
This indicates that tauopathies progress via a prion-like mechanism dependent upon tau oligomers (Gerson and Kayed, 2013; Castillo-Carranza et al., 2014b)
With this concept, tau may be able to translocate between neurons and augment toxic tau components; in fact, evidence suggests probability of tau oligomer propagation between synaptically connected neurons (Gendreau and Hall, 2013; Pooler et al., 2013b)
Further, mice injected with tau oligomers in the proximity of the hippocampus experienced immediate memory impairment (Lasagna-Reeves et al., 2011)
The study discovered that APFs form after tau oligomer formation and bypass higher NFT aggregate formation
Oligomeric tau intermediates decrease cell viability (Flach et al., 2012)
Recently, data has shown that injected tau oligomers colocalize with the mitochondrial marker porin, suggesting a pathological relationship
Also, data shows low levels of complex I in brain hemispheres injected with tau oligomers when compared to brains injected with monomers or fibrils
These results imply that tau oligomers initially affect complex I activity and may directly or indirectly disturb the later stage of complex V ATP synthesis (Lasagna-Reeves et al., 2011)
Hemispheres injected with tau oligomers were found to have increased levels of caspase-9 activation (Lasagna-Reeves et al., 2011)
Suggestively, as tau oligomers concentrate at the mitochondrial membrane, cytochrome C is released, leading to caspase-9 activation via a complex with apoptotic-peptidase activating- factor-1 (Apaf-1; Li et al., 1997)
HSPGs are ubiquitously expressed in many cell types including neurons, and have been previously associated with dense core plaques, cerebrovascular amyloid, and NFT formation (van Horssen et al., 2001)
Consistently, HSPGs have been implicated in amyloid as well as tau fibril formation in vitro, presumably facilitated by anionic moieties
However, regardless of the multiple “sizes” of tau aggregates that interact with the cell surface via HSPGs, it is likely that an assembly of at least three tau molecules is required to initiate endocytosis via HSPGs (Mirbaha et al., 2015)
In other words, the HSPGs serve as a receptor for the cellular uptake of tau, a critical step similar to prion-like propagation
AD brain samples contain exosomal proteins within amyloid plaques hinting that exosomes play part in disease pathology (Rajendran et al., 2006)
In support, tau associated with exosomes and phosphorylated at Thr-181 (AT270+ tau) has been identified in human CSF samples of AD patients
This hints that tau plays a role in monitoring intracellular signaling pathways (Pooler and Hanger, 2010)
In aging, a protein involved in mitochondrial fission, dynamin-related protein 1 (DRP1), can bind tau abnormally, inducing neurodegeneration via mitochondrial dysfunction (Figure 2; DuBoff et al., 2012)
In AD, tau pathology and neuronal cell loss coincide in the same brain regions, and as brain dysfunction progresses, NFTs are found in greater anatomical distributions (Ihara, 2001)
While evidence has linked FTD with parkinsonism in patients to tau mutations on chromosome 17 (FTDP-17), implying that tau dysfunction alone can cause neurodegeneration (Reed et al., 2001), studies in animal models have shown that overexpression of tau can lead to cell death (Lee et al., 2001; Tanemura et al., 2001, 2002; Tatebayashi et al., 2002) and exhibit behavioral abnormalities and synaptic dysfunction without the presence of NFTs (Wittmann et al., 2001; Andorfer et al., 2003; Santacruz et al., 2005; Spires et al., 2006; Berger et al., 2007; Yoshiyama et al., 2007; Cowan et al., 2010)
Recently, tau was discovered in the interstitial fluid of awake, wild-type mice, suggesting its release by neurons in the absence of neurodegeneration (Yamada et al., 2011)
Further, transgenic mouse lines expressing human tau aggregates in the entorhinal cortex have shown that tau is mislocalized from axons to cell bodies and dendrites as the mice age (Pooler et al., 2013b)
In the latter theory, during the secretion, vesicles and the cell membrane can be fused and uncoated tau protein can be released to the extracellular space (Clavaguera et al., 2009; Iba et al., 2013)
Previous studies suggest that uptake of aggregated tau from the extracellular space depends on interaction with heparan sulfate proteoglycans (HSPGs; Holmes and Diamond, 2014)
Basically, pathogenic tau aggregates use HSPGs to bind the cell surface of a neuron. This actively stimulates macropinocytosis, leading to propagation of aggregates between cells in culture and aggregate uptake in vivo (Holmes et al., 2013)
While functional tau is an unfolded monomeric protein that stabilizes microtubules, regulates neurite growth, and monitors axonal transport of organelles (Medina and Avila, 2014), dysfunctional tau acquires a new toxic function
In AD, the quantity of tau identified in the CSF increases with disease progression (Hampel et al., 2010). However, the mechanism of tau propagation from the brain to the CSF remains elusive
More recently, patients affected with FTD and AD, were found to have high levels of total tau and phosphorylated tau (p-T181 and p-S396; Saman et al., 2012)
Tau may be endocytosed, promoting an increase in intracellular calcium that results in neuronal death
In other words, it is sensible to theorize that tauopathies progress via interaction of extracellular tau with M1 and M3 receptors on neurons leading to cytotoxic effects (Gómez-Ramos et al., 2009)
Another study showed that expression of tau (truncated at Asp-421 to mimic caspase cleavage) caused mitochondrial dysfunction (Quintanilla et al., 2009)
Hyper-phosphorylated tau assembles into small aggregates known as tau oligomers in route of NFT formation
As hyperphosphorylated tau dislodges from microtubules, its affinity for other tau monomers leads individual tau to bind each other, forming oligomeric tau, a detergent-soluble aggregate
In AD, tau pathology has been found to spread from the transentorhinal cortex to the neocortex in a sequential pathway
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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.