Tau immunotherapy modulates both pathological tau and upstream amyloid pathology in an Alzheimer's disease mouse model.

In Alzheimer's disease (AD), the pathological accumulation of tau appears to be a downstream effect of amyloid ß protein (Aß). However, the relationship between these two proteins and memory loss is unclear. In this study, we evaluated the specific removal of pathological tau oligomers in aged Tg2576 mice by passive immunotherapy using tau oligomer-specific monoclonal antibody. Removal of tau oligomers reversed memory deficits and accelerated plaque deposition in the brain. Surprisingly, Aß*56 levels decreased, suggesting a link between tau and Aß oligomers in the promotion of cognitive decline. The results suggest that tau oligomerization is not only a consequence of Aß pathology but also a critical mediator of the toxic effects observed afterward in AD. Overall, these findings support the potential of tau oligomers as a therapeutic target for AD.

Passive immunization with Tau oligomer monoclonal antibody reverses tauopathy phenotypes without affecting hyperphosphorylated neurofibrillary tangles.

Recent findings suggest that tau oligomers, which form before neurofibrillary tangles (NFTs), are the true neurotoxic tau entities in neurodegenerative tauopathies, including Alzheimer's disease (AD). Studies in animal models of tauopathy suggest that tau oligomers play a key role in eliciting behavioral and cognitive impairments. Here, we used a novel tau oligomer-specific monoclonal antibody (TOMA) for passive immunization in mice expressing mutant human tau. A single dose of TOMA administered either intravenously or intracerebroventricularly was sufficient to reverse both locomotor and memory deficits in a mouse model of tauopathy for 60 d, coincident with rapid reduction of tau oligomers but not phosphorylated NFTs or monomeric tau. Our data demonstrate that antibody protection is mediated by extracellular and rapid peripheral clearance. These findings provide the first direct evidence in support of a critical role for tau oligomers in disease progression and validate tau oligomers as a target for the treatment of AD and other neurodegenerative tauopathies.

Rapid accumulation of endogenous tau oligomers in a rat model of traumatic brain injury: possible link between traumatic brain injury and sporadic tauopathies.

Traumatic brain injury (TBI) is a serious problem that affects millions of people in the United States alone. Multiple concussions or even a single moderate to severe TBI can also predispose individuals to develop a pathologically distinct form of tauopathy-related dementia at an early age. No effective treatments are currently available for TBI or TBI-related dementia; moreover, only recently has insight been gained regarding the mechanisms behind their connection. Here, we used antibodies to detect oligomeric and phosphorylated Tau proteins in a non-transgenic rodent model of parasagittal fluid percussion injury. Oligomeric and phosphorylated Tau proteins were detected 4 and 24 h and 2 weeks post-TBI in injured, but not sham control rats. These findings suggest that diagnostic tools and therapeutics that target only toxic forms of Tau may provide earlier detection and safe, more effective treatments for tauopathies associated with repetitive neurotrauma.

Amyloid-ß oligomers as a template for secondary amyloidosis in Alzheimer's disease.

Alzheimer's disease is a complex disease characterized by overlapping phenotypes with different neurodegenerative disorders. Oligomers are considered the most toxic species in amyloid pathologies. We examined human AD brain samples using an anti-oligomer antibody generated in our laboratory and detected potential hybrid oligomers composed of amyloid-ß, prion protein, α-synuclein, and TDP-43 phosphorylated at serines 409 and 410. These data and in vitro results suggest that Aß oligomer seeds act as a template for the aggregation of other proteins and generate an overlapping phenotype with other neuronal disorders. Furthermore, these results could explain why anti-amyloid-ß therapy has been unsuccessful.

Identification of oligomers at early stages of tau aggregation in Alzheimer's disease.

Neurofibrillary tangles (NFTs) are a pathological hallmark of Alzheimer's disease (AD); however, the relationship between NFTs and disease progression remains controversial. Analyses of tau animal models suggest that phenotypes coincide with accumulation of soluble aggregated tau species but not the accumulation of NFTs. The pathological role of prefilamentous tau aggregates, e.g., tau oligomeric intermediates, is poorly understood, in part because of methodological challenges. Here, we engineered a novel tau oligomer-specific antibody, T22, and used it to elucidate the temporal course and biochemical features of oligomers during NFT development in AD brain. We found that tau oligomers in human AD brain samples were 4-fold higher than those in the controls. We also revealed the role of oligomeric tau conformers in pretangles, neuritic plaques, and neuropil threads in the frontal cortex tissue from AD brains; this analysis uncovers a consistent code that governs tau oligomerization with regard to degree of neuronal cytopathology. These data are the first to characterize the role of tau oligomers in the natural history of NFTs, and they highlight the suitability of tau oligomers as therapeutic targets in AD and related tauopathies.

Differential activation of the ER stress factor XBP1 by oligomeric assemblies.

Several neurodegenerative disorders are characterized by protein misfolding, a phenomenon that results in perturbation of cellular homeostasis. We recently identified the protective activity of the ER stress response factor XBP1 (X-box binding protein 1) against Amyloid-ß1-42 (Aß42) neurotoxicity in cellular and Drosophila models of Alzheimer's disease. Additionally, subtoxic concentrations of Aß42 soluble aggregates (oligomers) induced accumulation of spliced (active) XBP1 transcripts, supporting the involvement of the ER stress response in Aß42 neurotoxicity. Here, we tested the ability of three additional disease-related amyloidogenic proteins to induce ER stress by analyzing XBP1 activation at the RNA level. Treatment of human SY5Y neuroblastoma cells with homogeneous preparations of α-Synuclein (α-Syn), Prion protein (PrP106-126), and British dementia amyloid peptide (ABri1-34) confirmed the high toxicity of oligomers compared to monomers and fibers. Additionally, α-Syn oligomers, but not monomers or fibers, demonstrated potent induction of XBP1 splicing. On the other hand, PrP106-126 and ABri1-34 did not activate XBP1. These results illustrate the biological complexity of these structurally related assemblies and argue that oligomer toxicity depends on the activation of amyloid-specific cellular responses.

The prion-like transmission of tau oligomers via exosomes.

The conversion and transmission of misfolded proteins established the basis for the prion concept. Neurodegenerative diseases are considered "prion-like" disorders that lack infectivity. Among them, tauopathies are characterized by the conversion of native tau protein into an abnormally folded aggregate. During the progression of the disease, misfolded tau polymerizes into oligomers and intracellular neurofibrillary tangles (NFTs). While the toxicity of NFTs is an ongoing debate, the contribution of tau oligomers to early onset neurodegenerative pathogenesis is accepted. Tau oligomers are readily transferred from neuron to neuron propagating through the brain inducing neurodegeneration. Recently, transmission of tau oligomers via exosomes is now proposed. There is still too much to uncover about tau misfolding and propagation. Here we summarize novel findings of tau oligomers transmission and propagation via exosomes.

Preparation and characterization of neurotoxic tau oligomers.

Tau aggregation is a pathological hallmark of Alzheimer's disease, Parkinson's disease, and many other neurodegenerative disorders known as tauopathies. Tau aggregates take on many forms, and their formation is a multistage process with intermediate stages. Recently, tau oligomers have emerged as the pathogenic species in tauopathies and a possible mediator of amyloid-ß toxicity in Alzheimer's disease. Here, we use a novel, physiologically relevant method (oligomer cross-seeding) to prepare homogeneous populations of tau oligomers and characterize these oligomers in vitro. We show that both Aß and α-synuclein oligomers induce tau aggregation and the formation of ß-sheet-rich neurotoxic tau oligomers.

A toxic subset of soluble α-synuclein species in dementia with Lewy body.

This scientific commentary refers to 'Analysis of α-synuclein species enriched from cerebral cortex of humans with sporadic dementia with Lewy bodies', by Sanderson et al. (https://doi.org/10.1093/braincomms/fcaa010).

α-Synuclein Oligomers Induce a Unique Toxic Tau Strain.

BACKGROUND: The coexistence of α-synuclein and tau aggregates in several neurodegenerative disorders, including Parkinson's disease and Alzheimer's disease, raises the possibility that a seeding mechanism is involved in disease progression. METHODS: To further investigate the role of α-synuclein in the tau aggregation pathway, we performed a set of experiments using both recombinant and brain-derived tau and α-synuclein oligomers to seed monomeric tau aggregation in vitro and in vivo. Brain-derived tau oligomers were isolated from well-characterized cases of progressive supranuclear palsy (n = 4) and complexes of brain-derived α-synuclein/tau oligomers isolated from patients with Parkinson's disease (n = 4). The isolated structures were purified and characterized by standard biochemical methods, then injected into Htau mice (n = 24) to assess their toxicity and role in tau aggregation. RESULTS: We found that α-synuclein induced a distinct toxic tau oligomeric strain that avoids fibril formation. In vivo, Parkinson's disease brain-derived α-synuclein/tau oligomers administered into Htau mouse brains accelerated endogenous tau oligomer formation concurrent with increasing cell loss. CONCLUSIONS: Our findings provide evidence, for the first time, that α-synuclein enhances the harmful effects of tau, thus contributing to disease progression.

Tau oligomers mediate α-synuclein toxicity and can be targeted by immunotherapy.

BACKGROUND: We have evaluated the efficacy of targeting the toxic, oligomeric form of tau protein by passive immunotherapy in a mouse model of synucleinopathy. Parkinson's disease and Lewy body dementia are two of the most common neurodegenerative disorders and are primarily characterized by the accumulation of α-synuclein in Lewy bodies. However, evidence shows that smaller, oligomeric aggregates are likely the most toxic form of the protein. Moreover, a large body of research suggests that α-synuclein interacts with tau in disease and may act in a synergistic mechanism, implicating tau oligomers as a potential therapeutic target. METHODS: We treated seven-month-old mice overexpressing mutated α-synuclein (A53T mice) with tau oligomer-specific monoclonal antibody (TOMA) and a control antibody and assessed both behavioral and pathological phenotypes. RESULTS: We found that A53T mice treated with TOMA were protected from cognitive and motor deficits two weeks after a single injection. Levels of toxic tau oligomers were specifically decreased in the brains of TOMA-treated mice. Tau oligomer depletion also protected against dopamine and synaptic protein loss. CONCLUSION: These results indicate that targeting tau oligomers is beneficial for a mouse model of synucleinopathy and may be a viable therapeutic strategy for treating diseases in which tau and α-synuclein have a synergistic toxicity.

Tau Oligomers: Cytotoxicity, Propagation, and Mitochondrial Damage.

Aging has long been considered as the main risk factor for several neurodegenerative disorders including a large group of diseases known as tauopathies. Even though neurofibrillary tangles (NFTs) have been examined as the main histopathological hallmark, they do not seem to play a role as the toxic entities leading to disease. Recent studies suggest that an intermediate form of tau, prior to NFT formation, the tau oligomer, is the true toxic species. However, the mechanisms by which tau oligomers trigger neurodegeneration remain unknown. This review summarizes recent findings regarding the role of tau oligomers in disease, including release from cells, propagation from affected to unaffected brain regions, uptake into cells, and toxicity via mitochondrial dysfunction. A greater understanding of tauopathies may lead to future advancements in regards to prevention and treatment.

Cerebral Microvascular Accumulation of Tau Oligomers in Alzheimer's Disease and Related Tauopathies.

The importance of vascular contributions to cognitive impairment and dementia (VCID) associated with Alzheimer's disease (AD) and related neurodegenerative diseases is increasingly recognized, however, the underlying mechanisms remain obscure. There is growing evidence that in addition to Aß deposition, accumulation of hyperphosphorylated oligomeric tau contributes significantly to AD etiology. Tau oligomers are toxic and it has been suggested that they propagate in a "prion-like" fashion, inducing endogenous tau misfolding in cells. Their role in VCID, however, is not yet understood. The present study was designed to determine the severity of vascular deposition of oligomeric tau in the brain in patients with AD and related tauopathies, including dementia with Lewy bodies (DLB) and progressive supranuclear palsy (PSP). Further, we examined a potential link between vascular deposition of fibrillar Aß and that of tau oligomers in the Tg2576 mouse model. We found that tau oligomers accumulate in cerebral microvasculature of human patients with AD and PSP, in association with vascular endothelial and smooth muscle cells. Cerebrovascular deposition of tau oligomers was also found in DLB patients. We also show that tau oligomers accumulate in cerebral microvasculature of Tg2576 mice, partially in association with cerebrovascular Aß deposits. Thus, our findings add to the growing evidence for multifaceted microvascular involvement in the pathogenesis of AD and other neurodegenerative diseases. Accumulation of tau oligomers may represent a potential novel mechanism by which functional and structural integrity of the cerebral microvessels is compromised.

Tau Oligomers Associate with Inflammation in the Brain and Retina of Tauopathy Mice and in Neurodegenerative Diseases.

It is well-established that inflammation plays an important role in Alzheimer's disease (AD) and frontotemporal lobar dementia (FTLD). Inflammation and synapse loss occur in disease prior to the formation of larger aggregates, but the contribution of tau to inflammation has not yet been thoroughly investigated. Tau pathologically aggregates to form large fibrillar structures known as tangles. However, evidence suggests that smaller soluble aggregates, called oligomers, are the most toxic species and form prior to tangles. Furthermore, tau oligomers can spread to neighboring cells and between anatomically connected brain regions. In addition, recent evidence suggests that inspecting the retina may be a window to brain pathology. We hypothesized that there is a relationship between tau oligomers and inflammation, which are hallmarks of early disease. We conducted immunofluorescence and biochemical analyses on tauopathy mice, FTLD, and AD subjects. We showed that oligomers co-localize with astrocytes, microglia, and HMGB1, a pro-inflammatory cytokine. Additionally, we show that tau oligomers are present in the retina and are associated with inflammatory cells suggesting that the retina may be a valid non-invasive biomarker for brain pathology. These results suggest that there may be a toxic relationship between tau oligomers and inflammation. Therefore, the ability of tau oligomers to spread may initiate a feed-forward cycle in which tau oligomers induce inflammation, leading to neuronal damage, and thus more inflammation. Further mechanistic studies are warranted in order to understand this relationship, which may have critical implications for improving the treatment of tauopathies.

Tau Oligomers Derived from Traumatic Brain Injury Cause Cognitive Impairment and Accelerate Onset of Pathology in Htau Mice.

Tau aggregation is a pathological feature of numerous neurodegenerative disorders and has also been shown to occur under certain conditions of traumatic brain injury (TBI). Currently, no effective treatments exist for the long-term effects of TBI. In some cases, TBI not only induces cognitive changes immediately post-injury, but also leads to increased incidence of neurodegeneration later in life. Growing evidence from our lab and others suggests that the oligomeric forms of tau initiate the onset and spread of neurodegenerative tauopathies. Previously, we have shown increased levels of brain-derived tau oligomers in autopsy samples from patients diagnosed with Alzheimer's disease. We have also shown similar increases in tau oligomers in animal models of neurodegenerative diseases and TBI. In the current study, we evaluated the presence of tau oligomers in blast-induced TBI. To test the direct impact of TBI-derived tau oligomer toxicity, we isolated tau oligomers from brains of rats that underwent either a blast- or a fluid percussion injury-induced TBI. Oligomers were characterized biochemically and morphologically and were then injected into hippocampi of mice overexpressing human tau (Htau). Mice were cognitively evaluated and brains were collected for immunological analysis after testing. We found that tau oligomers form as a result of brain injury in two different models of TBI. Additionally, these oligomers accelerated onset of cognitive deficits when injected into brains of Htau mice. Tau oligomer levels increased in the hippocampal injection sites and cerebellum, suggesting that tau oligomers may be responsible for seeding the spread of pathology post-TBI. Our results suggest that tau oligomers play an important role in the toxicity underlying TBI and may be a viable therapeutic target.

Tau Oligomers: The Toxic Player at Synapses in Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive disorder in which the most noticeable symptoms are cognitive impairment and memory loss. However, the precise mechanism by which those symptoms develop remains unknown. Of note, neuronal loss occurs at sites where synaptic dysfunction is observed earlier, suggesting that altered synaptic connections precede neuronal loss. The abnormal accumulation of amyloid-ß (Aß) and tau protein is the main histopathological feature of the disease. Several lines of evidence suggest that the small oligomeric forms of Aß and tau may act synergistically to promote synaptic dysfunction in AD. Remarkably, tau pathology correlates better with the progression of the disease than Aß. Recently, a growing number of studies have begun to suggest that missorting of tau protein from the axon to the dendrites is required to mediate the detrimental effects of Aß. In this review we discuss the novel findings regarding the potential mechanisms by which tau oligomers contribute to synaptic dysfunction in AD.

Antibody against Small Aggregated Peptide Specifically Recognizes Toxic Aß-42 Oligomers in Alzheimer's Disease.

Amyloid-beta (Aß) oligomers have emerged as the most toxic species in Alzheimer's disease (AD) and other amyloid pathologies. Also, Aß-42 peptide is more aggregation-prone compared to other Aß isoforms. Thus, we synthesized a small peptide of repeated sequence containing the last three amino acids, Val-40, Ile-41, and Ala-42 of Aß-42 that was subsequently aggregated and used to generate a novel antibody, VIA. In this study, we examined human AD and Tg2576 mouse brain samples using VIA in combination with other amyloid-specific antibodies and confirmed the specificity of VIA to oligomeric Aß-42. Moreover, we found that VIA does not recognize classic amyloid plaques composed of fibrillar Aß or Aß-40 ex vivo. Since VIA recognizes a distinct epitope specific to Aß-42 oligomers, it may have broad use for examining the accumulation of these oligomers in AD and other neurodegenerative diseases. VIA may also be used in immunotherapy studies to prevent neurodegenerative effects associated with Aß-42 oligomers.

Pathological interface between oligomeric alpha-synuclein and tau in synucleinopathies.

BACKGROUND: Aberrant accumulation of α-synuclein constitutes inclusion bodies that are considered a characteristic feature of a group of neurological disorders described as synucleinopathies. Often, multiple disease-causing proteins overlap within a given disease pathology. An emerging body of research focuses on the oligomeric populations of various pathogenic proteins, considering them as the culprits causing neuronal damage and degeneration. To this end, the use of conformation-specific antibodies has proven to be an effective tool. Previous work from our laboratory and others has shown that oligomeric entities of α-synuclein and tau accumulate in their respective diseases, but their interrelationship at this higher order has yet to be shown in synucleinopathies. METHODS: Here, we used two novel conformation-specific antibodies, F8H7 and Syn33, which recognize α-synuclein oligomers and were developed in our laboratory. We investigated brain tissue from five of each Parkinson's disease and dementia with Lewy bodies patients by performing biophysical and biochemical assays using these antibodies, in addition to the previously characterized anti-tau oligomer antibody T22. RESULTS: We demonstrate that in addition to the deposition of oligomeric α-synuclein, tau oligomers accumulate in these diseased brains compared with control brains. Moreover, we observed that oligomers of tau and α-synuclein exist in the same aggregates, forming hybrid oligomers in these patients' brains. CONCLUSIONS: In addition to the deposition of tau oligomers, our results also provide compelling evidence of co-occurrence of α-synuclein and tau into their most toxic forms, i.e., oligomers suggesting that these species interact and influence each other's aggregation via an interface in synucleinopathies.

Advances in therapeutics for neurodegenerative tauopathies: moving toward the specific targeting of the most toxic tau species.

Neurodegenerative disease is one of the greatest health concerns today and with no effective treatment in sight, it is crucial that researchers find a safe and successful therapeutic. While neurofibrillary tangles are considered the primary tauopathy hallmark, more evidence continues to come to light to suggest that soluble, intermediate tau aggregates--tau oligomers--are the most toxic species in disease. These intermediate tau species may also be responsible for the spread of pathology, suggesting that oligomeric tau may be the best therapeutic target. Here, we summarize results for the modulation of tau by molecular chaperones, small molecules and aggregation inhibitors, post-translational modifications, immunotherapy, other techniques, and future directions.

Immunotherapy for the treatment of Alzheimer's disease: amyloid-ß or tau, which is the right target?

Alzheimer's disease (AD) is characterized by the presence of amyloid plaques composed mainly of amyloid-ß (Aß) protein. Overproduction or slow clearance of Aß initiates a cascade of pathologic events that may lead to formation of neurofibrillary tangles, neuronal cell death, and dementia. Although immunotherapy in animal models has been demonstrated to be successful at removing plaques or prefibrillar forms of Aß, clinical trials have yielded disappointing results. The lack of substantial cognitive improvement obtained by targeting Aß raises the question of whether or not this is the correct target. Another important pathologic process in the AD brain is tau aggregation, which seems to become independent once initiated. Recent studies targeting tau in AD mouse models have displayed evidence of cognitive improvement, providing a novel therapeutic approach for the treatment of AD. In this review, we describe new advances in immunotherapy targeting Aß peptide and tau protein, as well as future directions.