PubMed: 28420982

Tau Oligomers: Cytotoxicity, Propagation, and Mitochondrial Damage.
Frontiers in aging neuroscience
Castillo-Carranza DL | Guerrero-Muñoz MJ | Shafiei SS

Evidence 995ebefd9c

In fact, tau oligomers might disrupt microtubule stability and trafficking, thus affecting organelle distribution

Evidence 17bd8cc8e3

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)

Evidence 152bbf5cb1

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)

Evidence 582b5f61f2

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)

Evidence e934bd3618

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)

Evidence a62d8eae49

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)

Evidence e2365a0a25

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)

Evidence c0a769a16b

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)

Evidence de2849337d

Hence, tau APFs may play a significant role in tauopathies by linking pore formation to cell death

Evidence e42e5006d8

As these granular tau oligomers fuse together, they form tau fibrils, which ultimately form NFTs (Takashima, 2013)

Evidence 8ce4bbccc5

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

Evidence 69522f07fd

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)

Evidence 45e5f3e214

These studies demonstrate that tau oligomers may be the toxic entities responsible for neurodegeneration in tauopathies (Ward et al., 2012

Evidence 4fa090eacf

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)

Evidence 2f3e7efb37

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)

Evidence b6aff121b8

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)

Evidence 2300e12bfc

This indicates that tauopathies progress via a prion-like mechanism dependent upon tau oligomers (Gerson and Kayed, 2013; Castillo-Carranza et al., 2014b)

Evidence c15475983a

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)

Evidence f445a1d294

Further, mice injected with tau oligomers in the proximity of the hippocampus experienced immediate memory impairment (Lasagna-Reeves et al., 2011)

Evidence d51189e6ed

The study discovered that APFs form after tau oligomer formation and bypass higher NFT aggregate formation

Evidence ffdbcbb3ed

Oligomeric tau intermediates decrease cell viability (Flach et al., 2012)

Evidence a959d632d6

Recently, data has shown that injected tau oligomers colocalize with the mitochondrial marker porin, suggesting a pathological relationship

Evidence e226249543

Also, data shows low levels of complex I in brain hemispheres injected with tau oligomers when compared to brains injected with monomers or fibrils

Evidence 9e2fc9d91f

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)

Evidence 9a1e592e94

Hemispheres injected with tau oligomers were found to have increased levels of caspase-9 activation (Lasagna-Reeves et al., 2011)

Evidence 68de1cd5e2

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)

Evidence e2a353e6d0

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)

Evidence 96f9d19256

Consistently, HSPGs have been implicated in amyloid as well as tau fibril formation in vitro, presumably facilitated by anionic moieties

Evidence b384ca363b

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)

Evidence 6de26b34e3

In other words, the HSPGs serve as a receptor for the cellular uptake of tau, a critical step similar to prion-like propagation

Evidence 8b6336d5ef

AD brain samples contain exosomal proteins within amyloid plaques hinting that exosomes play part in disease pathology (Rajendran et al., 2006)

Evidence 6c1f48a044

In support, tau associated with exosomes and phosphorylated at Thr-181 (AT270+ tau) has been identified in human CSF samples of AD patients

Evidence e891659347

This hints that tau plays a role in monitoring intracellular signaling pathways (Pooler and Hanger, 2010)

Evidence 803da88f7d

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)

Evidence e90add2e1f

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)

Evidence 582b03005c

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)

Evidence c7c77b3fea

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)

Evidence a9aa1beb0b

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)

Evidence 2e95f94e94

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)

Evidence d94cf2af76

Previous studies suggest that uptake of aggregated tau from the extracellular space depends on interaction with heparan sulfate proteoglycans (HSPGs; Holmes and Diamond, 2014)

Evidence ee788b5883

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)

Evidence b2749a4357

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

Evidence e2a7a7c5a2

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

Evidence bc03fe81dd

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)

Evidence c16d1a8017

Tau may be endocytosed, promoting an increase in intracellular calcium that results in neuronal death

Evidence a77c09bae6

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)

Evidence a2fcf7d5bb

Another study showed that expression of tau (truncated at Asp-421 to mimic caspase cleavage) caused mitochondrial dysfunction (Quintanilla et al., 2009)

Evidence c147601396

Hyper-phosphorylated tau assembles into small aggregates known as tau oligomers in route of NFT formation

Evidence 288d8524a0

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

Evidence d00c63f02d

In AD, tau pathology has been found to spread from the transentorhinal cortex to the neocortex in a sequential pathway


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